Aminoalkoxy-functional chalcones

ABSTRACT

The invention provides novel alkoxyaminochalcone derivatives and analogues thereof. Use of the compounds, or compositions comprising them, as pharmaceutically active agents, in particular against bacterial and parasitic infections, is also disclosed. The invention further relates to a method for detecting inhibitory effects against e.g., bacteria, parasites, fungi, and helminths. The chalcones of the invention carry amino substituents and exhibit enhanced biological effects combined with improved metabolic and physicochemical properties, making the compounds useful as drug substances, in particular as antiparasitic, bacteriostatic, and bacteriocidal agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage of International Application No.PCT/DK/03/00332, filed 19 May 2003, which claimed priority from DenmarkApplications PA 2002 00762, filed 17 May 2002, PA 2002 00763, filed 17May 2002, and PA 2002 01114, filed 18 Jul. 2002. The entire contents ofthe above-identified International Application and the DenmarkApplications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a novel class of chalcone derivativesand analogues thereto as well as to use of a class of chalconederivatives as pharmaceutically, active agents, in particular againstbacterial and parasitic infections.

Furthermore, the invention relates to a method of predicting whether achemical compound has a potential inhibitory effect against an organismsuch as Helicobacter pylori and Plasmodium falciparum. The prediction isbased on the ability of the chemical compound to act as an inhibitior ofthe enzyme dihydroorotate dehydrogenase which is involved in thesynthesis of pyrimidine in prokaryotic as well as eukaryotic cells suchas bacteria; parasites, fungi, helminths and any type of mammalian cellssuch as human cells.

BACKGROUND OF THE INVENTION

Chalcones, e.g., for use against parasitic infections are known fromearlier patent applications assigned to the applicant, e.g. WO 93/17671and WO 99/00114.

Moderate antibacterial activity has been reported for a limited numberof chalcones in earlier publications, e.g. Haraguchi, H. et alPhytochemistry 1998, 48, 125-129 and Hatano, T. et al Chem. Pharm. Bull(Tokyo) 2000,48, 1286-92.

The bioavailability of several of the known chalcones is low due to thelow solubility of the compounds. The compounds do not typically dissolvein the intestine and are therefore not available for absorption.

The spread of antimicrobial resistance determinants particular amongnosocomial bacterial pathogens is an increasing problem. Such resistantpathogens include Staphylococcus aureus resistant to methicillin andthus to all β-lactam-antibiotics and Enterococci resistant to vancomycin(VRE). Such resistant bacteria pose a significant therapeutic challengeand bacterial strains resistant to all currently availableantimicrobials are emerging. Furthermore, bacterial speciesintrinsically resistant to commonly employed antimicrobials are beingrecognized as important opportunistic pathogens in the setting oflong-term immunocompromized patients. An example of this isStenotrophomonas maltophilia which possesses a β-lactamase rendering thebacteria intrinsically resistant to carbapenems. As cross-resistancewithin a given class of antibiotics often occurs the development of newclasses of antibiotics is a necessity to counter the emerging threat ofbacterial resistance.

The resistance of Plasmodium falciparum to chloroquine and otherantimalarial drugs have created an urgent need for new drugs that aresafe and effective for the prophylaxis and treatment of malaria.

Furthermore, the increasing appearance of resistance to first lineantileishmanial drugs, e.g. Pentostam or Glucantime, emphasizes the needfor new drugs for the treatment of Leishmania infections.

Thus, there is a need for chalcone derivatives with improved therapeuticor prophylactic activities against parasites and bacteria.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the general synthetic scheme for the preparation ofaminoalkoxy-functional chalcones where the aromatic rings are phenylrings. R¹, R² and Z are as defined herein.

FIG. 2 illustrates a time-kill curve of C023 against S.aureus ATCC33591.Bacterial growth is inhibited at concentrations at or above the MIC(MIC=9.4 μM). As CFU counts per ml decreases at concentrations ofcompound above the MIC, the compound is bactericidal. The reduction inCFU/ml is faster as the concentration of test compound increases abovethe MIC. This indicates that the bactericidal action of the compound isprimarily dependent on the concentration of the test compound.

FIG. 3 illustrates a time-kill curve of C030 against S.aureus ATCC29213.Bacterial growth is inhibited at concentrations at or above the MIC(MIC=18.8 μM). As CFU counts per ml decreases at concentrations ofcompound above the MIC, the compound is bactericidal. The reduction inCFU/ml is faster as the concentration of test compound increases abovethe MIC. This indicates that the bactericidal action of the compound isprimarily dependent on the concentration of the test compound.

FIG. 4 illustrates a dose-response curve of LicA and one of the novelaminoalkoxy-chalcones (C130) at Plasmodium falciparum. As shown in thefigure, C130 is 213 times more potent than LicA.

FIG. 5 illustrates a dose-respons curve of LicA and one of the novelchalcones (C019) at Leishmania Major. As shown at the figure, C019 is100 times more potent than LicA.

FIG. 6 illustrates an effect curve of C035 in Plasmodium berghei K173infected NMRI female mice following multiple intra venousadministrations. As shown at the figure, treatment with C035 causes asignificant decrease in the parasitaemia.

FIG. 7 illustrates an effect curve of C114, C119, C128, C130 inPlasmodium berghei K173 infected NMRI female mice following multipleoral administrations. As shown at the figure, treatments with thesechalcones inhibit the development of the infection.

DESCRIPTION OF THE INVENTION

In an attempt to identify novel antimicrobial or antiparasitic agents,the present inventors have found that the aminoalkoxy-functionalchalcones defined herein exhibit interesting biological propertiescombined with improved metabolic and physicochemical properties whichmake the compounds useful as drug substances, in particular asantiparasitic agents, bacteriostatic agents, and bacteriocidal agents.

It is believed that the aminoalkoxy group or groups of theaminoalkoxy-functional chalcone will be charged according to pH of themedium and the pKa of the compound. The aqueous solubility of thecharged form is significantly higher than the solubility of the neutralspecies. As the aminoalkoxy-functional chalcones will be partiallycharged (i.e. soluble) at physiologically relevant pH values, e. g. inthe intestine and stomach, they will dissolve in the gastric juices andbe available for absorption. The bioavailability of theaminoalkoxy-functional chalcones will therefore be improved compared tothe known neutral chalcones, thus making the compounds generally usefulas drug candidates. Also, the present aminoalkoxy-functional chalconesdisplay a range of pKa values which allows the selection of a chalconederivative with optimal charged/non-charged ratio at a given pH value.

The introduction of an alifatic amino-group and hence a positive charge(at the pH value of the target site) affects the mode of interactionwith the biological target. It is anticipated that the compoundsinteract with the target in a different way than neutral chalcones, dueto the possibility of strong electrostatic interactions (attraction aswell as repulsion). This is indeed reflected in the activity of thecompounds, being more potent than the previously described neutralchalcones.

Furthermore, the application of the known chalcones as drug candidateshave been limited due to the extensive metabolism of the compoundsresulting in short half-lives in vivo. The inventors have now found thatintroduction of an aminoalkoxy group in the chalcone molecule changesthe metabolic properties so as to achieve improved metabolic stability.

Of particular interest, the present inventors have found that theamino-functional chalcones defined herein are far more potent againstmalaria and leishmania parasites than the earlier described neutralchalcone compounds, and that they exhibit excellent bacteriocidal andbacteriostatic properties, even against multi-resistant bacteriastrains.

Thus, in a first aspect, the present invention provides chalconederivatives and analogues of the general formula:(Y¹)_(m)—Ar¹(X¹)—C(═O)VAr²(X²)—(Y²)_(p)and salts thereof,

-   wherein Ar¹ and Ar² may independently be selected from aryl or    heteroaryl;-   V designates —CH₂—CH₂—, —CH═CH— or —C═C—, preferably —CH═CH—;-   m is 0, 1, or 2,-   p is 0, 1, or 2,-   wherein the sum of m and p is at least 1;-   each Y¹ independently may represent an aminoalkoxy-functional    substituent of the formula    —O-Z-N(R¹)R²,-   each Y² independently may represent an aminoalkoxy-functional    substituent of the formula    —O-Z-N(R¹)R²,-   wherein Z is a biradical —(C(R^(H))₂)_(n)—, wherein n is an integer    in the range of 1-6, preferably 2-4, such as 2-3, and each R^(H) is    independently selected from hydrogen or C₁₋₆-alkyl;-   R¹ and R² may independently be selected from hydrogen, optionally    substituted C₁₋₁₂-alkyl, optionally substituted C₂₋₁₂-alkenyl,    optionally substituted C₄₋₁₂-alkadienyl, optionally substituted    C₆₋₁₂-alkatrienyl, optionally substituted C₂₋₁₂-alkynyl, optionally    substituted C₁₋₁₂-alkoxycarbonyl, optionally substituted    C₁₋₁₂-alkylcarbonyl, optionally substituted aryl, optionally    substituted aryloxycarbonyl, optionally substituted arylcarbonyl,    optionally substituted heteroaryl, optionally substituted    heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl,    aminocarbonyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,    amino-C₁₋₆-alkyl-aminocarbonyl, or mono- and    di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl; or R¹ and R² together    with the nitrogen atom to which they are attached (—N(R¹)R²) form an    optionally substituted nitrogen-containing heterocyclic ring;-   X¹ may designate 0-5, preferably 0-4, such as 0-3, e.g. 0-2,    substituents, and X² may designate 1-5, preferably 1-4, such as 1-3,    e.g. 1-2 substituents, where such substituents independently may be    selected from optionally substituted C₁₋₁₂ alkyl, optionally    substituted C₂₋₁₂alkenyl, optionally substituted C₄₋₁₂-alkadienyl,    optionally substituted C₆₋₁₂-alkatrienyl, optionally substituted    C₂₋₁₂alkynyl, hydroxy, optionally substituted C₁₋₁₂-alkoxy,    optionally substituted C₂₋₁₂-alkenyloxy, carboxy, optionally    substituted C₁₋₁₂-alkoxycarbonyl, optionally substituted    C₁₋₁₂-alkylcarbonyl, formyl, C₁₋₆-alkylsulphonylamino, optionally    substituted aryl, optionally substituted aryloxycarbonyl, optionally    substituted aryloxy, optionally substituted arylcarbonyl, optionally    substituted arylamino, arylsulphonylamino, optionally substituted    heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally    substituted heteroaryloxy, optionally substituted    heteroarylcarbonyl, optionally substituted heteroarylamino,    heteroarylsulphonylamino, optionally substituted heterocyclyl,    optionally substituted heterocyclyloxycarbonyl, optionally    substituted heterocyclyloxy, optionally substituted    heterocyclylcarbonyl, optionally substituted heterocyclylamino,    heterocyclylsulphonylamino, amino, mono- and di(C₁₋₆-alkyl)amino,    carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,    amino-C₁₋₆-alkyl-aminocarbonyl, mono- and    di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,    C₁₋₆-alkylcarbonylamino, amino-C₁₋₆-alkyl-carbonylamino, mono- and    di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-carbonylamino,    amino-C₁₋₆-alkyl-amino, mono- and    di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-amino, cyano, guanidino, carbamido,    C₁₋₆-alkanoyloxy, C₁ ₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl,    C₁₋₆-alkylsulphonyloxy, aminosulfonyl, mono- and    di(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substituted    C₁₋₆-alkylthio, or halogen, where any nitrogen-bound C₁₋₆-alkyl may    be substituted with hydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, amino,    mono- and di(C₂₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,    halogen, C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, or guanidine.

The substituents R¹ and R²carried by the nitrogen atom of theaminoalkoxy substituent, are believed to slightly alter the pKa value ofthe chalcone derivative. Thus, the particular selection of the groups R¹and R² may be used to fine-tune the pKa value in view of the particularcondition or disease and the intended route of administration.

In one embodiment, R¹ and R² may be independently selected fromhydrogen, optionally substituted C₁₋₁₂-alkyl, optionally substitutedC₂₋₁₂-alkenyl, optionally substituted C₂₋₁₂-alkynyl, optionallysubstituted C₁₋₁₂-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,aminocarbonyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, and mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl. In particular R¹ and R²are independently selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₁₋₆-alkylcarbonyl,heteroarylcarbonyl, aminocarbonyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, or mono-and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl.

In another embodiment, R¹ and R² together with the nitrogen atom towhich they are attached (—N(R¹)R²) may form an optionally substitutednitrogen-containing heterocyclic ring.

In still a further embodiment, X¹ may designate 0-4, such as 0-3, e.g.0-2, substituents, and X² may designate 1-4, such as 1-3, e.g. 1-2,substituents, where such optional substituents may independently beselected from optionally substituted C₁₋₁₂-alkyl, hydroxy, optionallysubstituted. C₁₋₁₂-alkoxy, optionally substituted C₂₋₁₂-alkenyloxy,carboxy, optionally substituted C₁₋₁₂-alkylcarbonyl, formyl,C₁₋₆-alkylsulphonylamino, optionally substituted aryl, optionallysubstituted aryloxycarbonyl, optionally substituted aryloxy, optionallysubstituted arylcarbonyl, optionally substituted arylamino,arylsulphonylamino, optionally substituted heteroaryl, optionallysubstituted heteroarylamino, optionally substituted heteroarylcarbonyl,optionally substituted heteroaryloxy, heteroarylsulphonylamino,optionally substituted heterocyclyl, optionally substitutedheterocyclyloxy, optionally substituted heterocyclylamino, amino, mono-and di(C₁₋₆-alkyl)amino, carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,amino-C₁₋₆-alkyl-carbonylamino, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-carbonylamino, amino-C₁₋₆-alkyl-amino,mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-amino, guanidino, carbamido,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, C₁₋₆-alkylsulphonyloxy,optionally substituted C₁₋₆-alkylthio, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, or halogen, where any nitrogen-boundC₁₋₆-alkyl may be substituted with hydroxy, C₁₋₆-alkoxy, and/or halogen.In particular, X¹ may designate 0-3, e.g. 0-2, substituents, and X²designates 1-3, e.g. 1-2, substituents, where such optional substituentsmay independently be selected from optionally substituted C₁₋₆-alkyl,hydroxy, optionally substituted C₁₋₆-alkoxy, carboxy, optionallysubstituted C₁₋₆-alkylcarbonyl, C₁₋₆-alkylsulphonylamino, optionallysubstituted aryl, optionally substituted aryloxy, optionally substitutedarylamino, arylsulphonylamino, optionally substituted heteroaryl,optionally substituted heteroarylamino, heteroarylsulphonylamino, amino,mono- and di(C₁₋₆-alkyl)amino, carbamoyl, C₁₋₆-alkylcarbonylamino,amino-C₁₋₆-alkyl-carbonylamino, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-carbonylamino, amino-C₁₋₆-alkyl-amino,mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-amino, guanidino, carbamido,optionally substituted C₁₋₆-alkylthio, optionally substitutedheterocyclyl, optionally substituted heterocyclyloxy, optionallysubstituted heterocyclylamino or halogen, where any nitrogen-boundC₁₋₆-alkyl may be substituted with hydroxy, C₁₋₆alkoxy, and/or halogen.

The group V is relevant with respect to the spatial orientation of therings Ar¹ and Ar². Thus, the group V may be —CH₂—CH₂—, —CH═CH— or —C═C—.In a currently particularly interesting embodiment V designates —CH═CH—.

In the context of the present invention the expression “chalconederivative” has been assigned to the compounds of the above formula inthat the overall structure namely Ar¹—C(═O)—C—C—Ar² resembles that ofthe chalcone structure: This being said, Ar¹ and Ar² are selected fromaromatic rings and heteroaromatic rings. It is currently believed thatparticularly interesting compounds are those where at least one of Ar¹and Ar², preferably both, are aryl, in particular phenyl. This beingsaid, the inventors envisage that the functionality of the compounds maybe substantially preserved (or even improved) when one or both of Ar¹and Ar² are heteroaromatic rings.

In one embodiment, at least one of Ar¹ and Ar² is selected fromthiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, thienyl, quinolyl, isoquinolyl, and indolyl.

In another embodiment, both of Ar¹ and Ar² are phenyl and Y² representsat least one aminoalkoxy-functional substituent, one of which beinglocated in the 2-position of the phenyl ring, and X² represents at leastone substituent, one of which being located in the 4- or 5-position ofthe phenyl ring.

In yet another embodiment, both of Ar¹ and Ar² are phenyl and Y²represents at least one aminoalkoxy-functional substituent, one of whichbeing located in the 3-position of the phenyl ring, and X² represents atleast one substituent, one of which being located in the 5-position ofthe phenyl ring.

In a further embodiment, X² represents at least one substituent selectedfrom C₁₋₆-alkyl, hydroxy, C₁₋₆-alkoxy, C₁₋₆-alkylcarbonyl, optionallysubstituted aryl, optionally substituted aryloxy, optionally substitutedarylamino, optionally substituted heteroaryl, optionally substitutedheteroarylamino, mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino,optionally substituted C₁₋₆-alkylthio, optionally substitutedheterocyclyl, optionally substituted heterocyclyloxy, optionallysubstituted heterocyclylamino or halogen, in particular from C₁₋₆-alkyl,optionally substituted phenyl, or hydroxy, e.g. from C₁₋₆-alkyl oroptionally substituted phenyl. Such compounds have shown excellentbacteriostatic and bacteriocidal effects as well as antiparasiticeffects (see the Examples).

In a further embodiment, which may combined with other embodimentsherein, both of Ar¹ and Ar² are optionally substituted phenyl, and X¹represents at least one substituent, one of which being located in the2- or 3-position of the phenyl ring, and preferably being selected fromamino-C₁₋₆-alkyl or mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl. Suchcompounds have shown excellent as antiparasitic effects (see theExamples).

In a still further embodiment, which may combined with other embodimentsherein, both of Ar¹ and Ar² are phenyl, and X¹ represents at least onesubstituent, one of which being located in the 4-position of the phenylring, and preferably being selected from hydroxy, amino-C₁₋₆-alkylaminoor mono-, and di(C₁₋₆-alkyl)amino-C₁₋₆-alkylamino. Such compounds havealso shown excellent as antiparasitic effects (see the Examples).

The group Z is typically a biradical —(C(R^(H))₂)_(n)—, wherein n is aninteger in the range of 1-6, preferably 2-4, such as 2-3, wherein eachR^(H) may independently be selected from hydrogen or C₁₋₆-alkyl. Aparticular example of Z is —(CH₂)_(n)— wherein n is 2-4, such as 2-3.

Thus, in a particular embodiment, one of Y¹ and Y² represents asubstituent of the formula—O—(CH₂)₂₋₃—N(R¹)R²wherein R¹ and R² may be selected from hydrogen or C₁₋₆-alkyl.Furthermore, V is preferably —CH═CH—, and Ar¹ and Ar² are bothoptionally substituted phenyl.

In one preferred embodiment, m is 1 and p is 0. 1in another preferredembodiment m is 0 and p is 1. In a further interesting embodiment, m andp are both 1.

In an additional interesting embodiment, one or both of X¹ and X²independently designates one optionally substituted C₁₋₁₂-alkyl group ofthe formula-A-N(R^(k))R^(m)wherein A is a biradical —(C(R^(H))₂)_(n)—, wherein n is an integer inthe range of 1-6, preferably 1-4, such as 1-3, and each R^(H) isindependently selected from hydrogen or C₁₋₆-alkyl, and R^(k) and R^(m)may independently be selected from hydrogen, optionally substitutedC₁₋₁₂-alkyl, optionally substituted C₂₋₁₂-alkenyl, optionallysubstituted C₄₋₁₂-alkadienyl, optionally substituted C₆₋₁₂-alkatrienyl,optionally substituted C₂₋₁₂-alkynyl, optionally substitutedC₁₋₁₂-alkoxycarbonyl, optionally substituted C₁₋₁₂-alkylcarbonyl,optionally substituted aryl, optionally substituted aryloxycarbonyl,optionally substituted arylcarbonyl, optionally substituted heteroaryl,optionally substituted heteroaryloxycarbonyl, optionally substitutedheteroarylcarbonyl, aminocarbonyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, or mono-and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl; or R^(k) and R^(m)together with the nitrogen atom to which they are attached(—N(R^(k))R^(m)) may form an optionally substituted nitrogen-containingheterocyclic ring.

In another interesting embodiment, one or both of X¹ and x²independently designates one mono- ordi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-amino group of the formula—NR^(n)—B—N(R^(p))R^(q)wherein B is a biradical —(C(R^(H))₂)_(n)—, wherein n is an integer inthe range of 1-6, preferably 2-4, such as 2-3, and each R^(H) isindependently selected from hydrogen or C₁₋₆-6alkyl, or two R^(H) on thesame carbon atom may designate ═O;

-   R^(p) and R^(q) may independently be selected from hydrogen or    optionally substituted C₁₋₆-alkyl which may be substituted with    hydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy amino, mono- and    di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino, halogen,    C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, or guanidine;-   or R^(p) and R^(q) together with the nitrogen atom to which they are    attached (—N(R^(p))R^(q)) may form an optionally substituted    nitrogen-containing heterocyclic ring;-   R^(n) is selected from hydrogen or C₁₋₆-alkyl;-   or R^(p) and R^(n) may together form a biradical B* which is as    defined for B.

In a highly preferred embodiment, the compound of the general formulaabove may be selected from the group comprising

-   3-[2-(2-Dimethylamino-ethoxy)-phenyl]1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-5-hydroxy-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   N-(2-{3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-acryloyl}-phenyl)-benzenesulfonamide,-   3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   1-(2-Chloro-4-methoxy-phenyl    )-3-[4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-(4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   1-(2-Chloro-4-methoxy-phenyl)-3-[4-(2-dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-propenone,-   3-[2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   1-(2-Chloro-4-methoxy-phenyl)-3-[4-(2-dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(4,-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   1(2-Chloro-4-methoxy-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone,-   N-(2-{3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-acryloyl}-phenyl)-benzenesulfonamide,-   3-[3,5-Di-tert-butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-[1,1′;4′,1″]terphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   1-(2-Diethylaminomethyl-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-l1-[2-(4-methyl-piperazin-1ylmethyl)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-[2-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-[4-(2-dimethylamino-ethylamino)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(3-dimethylaminomethyl-phenyl)-propenone,-   3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(2-diethylaminomethyl-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-4-hydroxy-5-propyl-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(4-hydroxy-phenyl)-propenone,-   3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(4-hydroxy-phenyl)-propenone,-   N-(2-{3-[5-tert-Butyl-2-(3-dimethylamino-propoxy)-phenyl]-acryloyl}-phenyl)-benzenesulfonamide,-   3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   1-(2,4-Dimethoxy-phenyl)-3-[3-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   1-(2,5-Dimethoxy-phenyl)-3-[3-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-(2-methoxy-phenyl)-propenone,-   3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-(4-methoxy-phenyl)-propenone,-   3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-[2-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   3-[3-(3-Dimethylamino-propoxy)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   1-(2,4-Dimethoxy-phenyl)-3-[3-(3-dimethylamino-propoxy)-phenyl]-propenone,-   3-[3-(3-Dimethylamino-propoxy)-phenyl]-1-(2-methoxy-phenyl)-propenone,-   1-(2,5-Dimethoxy-phenyl)-3-[3-(3-dimethylamino-propoxy)-phenyl]-propenone,-   3-[3-(3-Dimethylamino-propoxy)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   1-(3-Dimethylaminomethyl-phenyl)-3-[3-(3-dimethylamino-propoxy)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-[2-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   1-[2-(2-Dimethylamino-ethoxy)-phenyl]-3-(3-dimethylaminomethyl-phenyl)-propenone,-   1-[2-(2-Dimethylamino-ethoxy)-phenyl]-3-(2-dimethylaminomethyl-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-[2-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-[2-(3-dimethylamino-propoxy)-phenyl]-propenone,-   3-(2,4-Dichloro-phenyl)-1-[2-(3-dimethylamino-propoxy)-phenyl]-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-[3-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   3-(2,5-Dimethoxy-phenyl)-1-[4-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-ethoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)2′-methyl-biphenyl-3-yl]-1-(2-ethoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-isopropoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-[2-(2-hydroxy-ethylamino)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[2-(2-hydroxy-ethylamino)-phenyl]-propenone,-   3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-[3-(3-dimethylamino-propoxy)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(4-fluoro-phenyl)-propan-1-one,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propan-1-one,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[2-(2-dimethylamino-ethylamino)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[3-(2-dimethylamino-ethylamino)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-{2-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-propenone,-   1-(2-Butoxy-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-fluoro-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-fluoro-phenyl)-propenone,-   1-(2-Bromo-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone,-   1-(3-Bromo-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone,-   1-(4-Bromo-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-hydroxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-hydroxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(4-hydroxy-phenyl)-propenone,-   1-(4-Cyclohexyl-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone,-   N-(3-{3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-acryloyl}-phenyl)-acetamide,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-4-methoxy-phenyl)-propenone,-   1-(2-Amino-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone,-   1-(4-Amino-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-[4-hydroxy-2-(4-methyl-piperazin-1-yl)-phenyl]-propenone,-   3-[2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(4-methoxy-phenyl)-propenone,-   3-[2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[4-hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[4-(2-dimethylamino-ethylamino)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[2-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-hexyloxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[3-(4-methyl-piperazin-1-yl)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[2-(3-dimethylamino-propoxy)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-fluoro-4-hydroxy-phenyl)-propenone,-   1-(6-Amino-benzo[1,3]dioxol-5-yl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-phenyl-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone,-   2-Dimethylamino-N-(3-{3-[4-(2-dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-(E)-acryloyl}-phenyl)-acetamide,-   3-[4-(4-Dimethylamino-butoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-5-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-3ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-5-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2-methyl-biphenyl-3-yl]-1-(2-imethylaminomethyl-4-methoxy-phenyl)-propenone,-   3-[5-(1,1-Dimethyl-allyl)-2-(2-dimethylamino-ethoxy)-phenyl]-1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-propenone,-   3-[5-(1,1-Dimethyl-allyl)-2-(2-dimethylamino-ethoxy)-phenyl]-1-(4-hydroxy-phenyl)-propenone,-   3-[6-(2-Dimethylamino-ethoxy)-2,3,3-trimethyl-2,3-dihydro-benzofuran-5-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-pyrrolidin-1-ylmethyl-phenyl)-propenone,-   1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl}-3-[4-(2-dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-trifluoromethoxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[2′-tert-Butoxymethyl-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′,5′-dimethoxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′,4′-dimethoxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′,4′,6′-trimethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methoxymethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′,6′-dimethoxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methylsulfanyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-trifluoromethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-hydroxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-ethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[2′,6′-Dichloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′,6′-difluoro-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-{4-[2-(tert-Butyl-methyl-amino)-ethoxy]-2′-methyl-biphenyl-3-yl}-1-(2-dimethylaminomethyl-phenyl)-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-[2′-methyl-4-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-3-yl]-propenone,-   3-[4-(2-Diethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(3-Dimethylamino-propoxy)-2′-methyl-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-(3-fluoro-4-hydroxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-fluoro-4-hydroxy-phenyl)-propenone,-   3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(3-fluoro-4-hydroxy-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-(3-fluoro-4-hydroxy-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-(3-fluoro-4-methoxy-phenyl)-propenone,-   3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(3-fluoro-4-methoxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-fluoro-4-methoxy-phenyl)-propenone,-   3-(2,4-Dichloro-phenyl)-1-[4-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   3-{4-[5-(tert-Butyl-methyl-amino)-pentyloxy]-2′-methyl-biphenyl-3-yl}-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(4-Diethylamino-butoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-{4-[4-(tert-Butyl-methyl-amino)-butoxy]-2′-methyl-biphenyl-3-yl}-1-(2-dimethylaminomethyl-phenyl)-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-[2′-methyl-4-(4-pyrrolidin-1-yl-butoxy)-biphenyl-3-yl]-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-[2′-methyl-4-(4-methylamino-butoxy)-biphenyl-3-yl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(4-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[4-hydroxy-2-(4piperazin-1-yl)-phenyl]-propenone,-   3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-[4-(2-dimethylamino-ethoxy)-2-(4-methyl-piperazin-1-yl)-phenyl]-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-fluoro-4-hydroxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[4-(2-dimethylamino-ethoxy)-2-fluoro-phenyl]-propenone,-   3-(2,4-Dichloro-phenyl)-1-[4-(2-dimethylamino-ethoxy)-2-fluoro-phenyl]-propenone,-   3-(2,4-Dichloro-phenyl)-1-[3-(2-dimethylamino-ethoxy)-phenyl]-propenone,-   3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(4-hydroxy-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(4-hydroxy-phenyl)-propenone,-   1-(2-Dimethylaminomethyl-phenyl)-3-[2′-methyl-4-(5-pyrrolidin-1-yl-pentyloxy)-biphenyl-3-yl]-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-5-pyridin-3-yl-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[2-(2-Dimethylamino-ethoxy)-5-pyridin-2-yl-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-3′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[3-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-4-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[2′-Bromo-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[4-(2-Dimethylamino-ethoxy)-4′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,-   3-[5-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,    and salts thereof.

While the above-mentioned group of compounds is intended to include allstereoisomers, including optical isomers, and mixtures thereof, as wellas pure, partially enriched, or, where relevant, racemic forms, agenerally preferred embodiment of the above-mentioned compounds has theE-configuration at the enone functionality.

The invention further provides combinatorial libraries, mixtures andkits for screening compounds as defined above.

In one aspect, a combinatorial library comprising at least two compoundsof the general formula is provided. Such library may be in the form ofan equimolar mixture, or in a mixture of any stoichiometry. Typicalembodiments comprise at least two, such as at least 10, such as at least100, such as at least 1000, such as at least 10000, such as at least100000 compounds as defined above.

In another aspect, combinatorial compound collections in the form ofkits for screening for biologically or pharmacologically activecompounds are provided. Such kits comprise at least two topologicallydistinct singular compounds of the general formula defined above.Typical kits comprise at least 10, such as at least 100, such as atleast 1000, such as at least 10000, such as at least 100000 compounds asdefined above. Kits are preferably provided in the form of solutions ofthe compounds in appropriate solvents.

Further provided are methods for screening for pharmacologically activecompounds, especially bacteriostatic; bacteriocidal and antiparasiticagents, consisting of the steps of preparing a kit or library comprisingat least two compounds of the general formula defined above, contactingsaid kit or library with a target molecule, such as a protein or nucleicacid, a target tissue, or a target organism, such as a bacterium orparasite, and detecting a biological or pharmacological response causedby at least one compound. Optionally, the steps may be repeated asappropriate to achieve deconvolution.

Definitions

In the present context, the term “bacteriostatic” is intended todescribe an antimicrobial activity of a test compund, characterized byan inhibition of bacterial growth in the absence of a reduction ofviable bacteria (bacterial kill) during incubation with the testcompound, as evidenced in the killing curve determination by astationary number of colony forming units, (CFU) during incubation time.

In the present context, the term “bacteriocidal” is intended to describean antimicrobial activity of a test compound, characterized by thereduction of viable bacteria (bacterial kill) during incubation with thetest compound, as evidenced in the killing curve determination by areduction of colony forming units (CFU) during incubation time.

In the present contest, the term “antiparasitic” is intended to describethe ability of a test compound to upon incubation in vitro with aculture of parasites, e.g. Leishmania major or Plasmodium falciparum, toinhibit metabolic labelling of the parasites by at least 50% compared tomock treated control cultures.

In the present context, the term “C₁₋₁₂-alkyl” is intended to mean alinear, cyclic or branched hydrocarbon group having 1 to 12 carbonatoms, such as methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl,tert-butyl, iso-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, etc. Analogously, the term “C₁₋₆-alkyl” is intended to meana linear, cyclic or branched hydrocarbon group having 1 to 6 carbonatoms, such as methyl, ethyl, propyl, iso-propyl, pentyl, cyclopentyl,hexyl, cyclohexyl, and the term “C₁-alkyl” is intended to cover linear,cyclic or branched hydrocarbon groups having 1 to 4 carbon atoms, e.g.methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl, iso-butyl,tert-butyl, cyclobutyl.

Whenever the term “C₁₋₁₂-alkyl” is used herein, it should be understoodthat a particularly interesting embodiment thereof is “C₁₋₆-alkyl”.

Similarly, the terms “C₂₋₁₂-alkenyl”, “C₄₋₁₂-alkadienyl”, and“C₆₋₁₂-alkatrienyl” are intended to cover linear, cyclic or branchedhydrocarbon groups having 2 to 12, 4 to 12, and 6 to 12, carbon atoms,respectively, and comprising one, two, and three unsaturated bonds,respectively. Examples of alkenyl groups are vinyl, allyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl. Examples ofalkadienyl groups are butadienyl, pentadienyl, hexadienyl, heptadienyl,heptadecadienyl. Examples of alkatrienyl groups are hexatrienyl,heptatrienyl, octatrienyl, and heptadecatrienyl. Preferred examples ofalkenyl are vinyl, allyl, butenyl, especially allyl.

Similarly, the term “C₂₋₁₂-alkynyl” is intended to mean a linear orbranched hydrocarbon group having 2 to 12 carbon atoms and comprising atriple bond. Examples hereof are ethynyl, propynyl, butynyl, octynyl,and dodecaynyl.

Whenever the terms “C₂₋₁₂-alkenyl”, “C₄₋₁₂-alkadienyl”,“C₆₋₁₂-alkatrienyl”, and “C₂₋₁₂-alkynyl” are used herein, it should beunderstood that a particularly interesting embodiment thereof are thevariants having up to six carbon atoms.

In the present context, i.e. in connection with the terms “alkyl”,“alkoxy”, “alkenyl”, “alkadienyl”, “alkatrienyl”, and “alkynyl”, theterm “optionally substituted” is intended to mean that the group inquestion may be substituted one or several times, preferably 1-3 times,with group(s) selected from hydroxy (which when bound to an unsaturatedcarbon atom may be present in the tautomeric keto form), C₁₋₆-alkoxy(i.e. C₁₋₆-alkyl-oxy), C₂₋₆-alkenyloxy, carboxy, oxo (forming a keto oraldehyde functionality), C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl,formyl, aryl, aryloxycarbonyl, aryloxy, arylamino, arylcarbonyl,heteroaryl, heteroarylamino, heteroaryloxycarbonyl, heteroaryloxy,heteroarylcarbonyl, amino, mono- and di(C₁₋₆-alkyl)amino, carbamoyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl,mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkylcarbonylamino, cyano, guanidino, carbamido,C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkanoyloxy, C₁₋₆-alkyl-sulphonyl,C₁₋₆-alkyl-sulphinyl, C₁₋₆-alkylsulphonyloxy, nitro, C₁₋₆-alkylthio,halogen, where any aryl and heteroaryl may be substituted asspecifically describe below for “optionally substituted aryl andheteroaryl”, and any alkyl, alkoxy, and the like representingsubstituents may be substituted with hydroxy, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidine.

Preferably, the substituents are selected from hydroxy (which when boundto an unsaturated carbon atom may be present in the tautomeric ketoform), C₁₋₆-alkoxy (i.e. C₁₋₆-alkyl-oxy), C₂₋₆-alkenyloxy, carboxy, oxo(forming a keto or aldehyde functionality), C₁₋₆-alkylcarbonyl, formyl,aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroarylamino,heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C₁₋₆-alkyl)amino;carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,guanidino, carbamido, C₁₋₆-alkyl-sulphonyl-amino, C₁₋₆-alkyl-sulphonyl,C₁₋₆-alkyl-sulphinyl, C₁₋₆-alkylthio, halogen, where any aryl andheteroaryl may be substituted as specifically describe below for“optionally substituted aryl and heteroaryl”.

Especially preferred examples are hydroxy, C₁₋₆alkoxy, C₂₋₆-alkenyloxy,amino, mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,halogen, C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, and guanidine.

“Halogen” includes fluoro, chloro, bromo, and iodo.

In the present context the term “aryl” is intended to mean a fully orpartially aromatic carbocyclic ring or ring system, such as phenyl,naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl,benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferredexample.

The term “heteroaryl” is intended to mean a fully or partially aromaticcarbocyclic ring or ring system where one or more of the carbon atomshave been replaced with heteroatoms, e.g. nitrogen (═N—or —NH—),sulphur, and/or oxygen atoms. Examples of such heteroaryl groups areoxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,coumaryl, furyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl,benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl,tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl,benzopyrazolyl, phenoxazonyl. Particularly interesting heteroaryl groupsare oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl,thienyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, indolyl inparticular pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, thienyl,quinolyl, tetrazolyl, and isoquinolyl.

The term “heterocyclyl” is intended to mean a non-aromatic carbocyclicring or ring system where one or more of the carbon atoms have beenreplaced with heteroatoms, e.g. nitrogen (═N—or —NH—), sulphur, and/oroxygen atoms. Examples of such heterocyclyl groups are imidazolidine,piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane,diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine,azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine,dihydroazepine, tetrahydroazepine, and hexahydroazepine, oxazolane,oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane,oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran,oxepane, tetrahydrothiophene, tetrahydrothiopyrane, thiepane, dithiane,dithiepane, dioxane, dioxepane, oxathiane, oxathiepane. The mostinteresting examples are imidazolidine, piperazine, hexahydropyridazine,hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine,azepane, azocane, azetidine, tropane, oxazinane (morpholine), oxazolane,oxazepane, thiazolane, thiazinane, and thiazepane, in particularimidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine,diazepane, pyrrolidine, piperidine, azepane, oxazinane (morpholine), andthiazinane.

In the present context, i.e. in connection with the terms “aryl”,“heteroaryl”, and heterocyclyl, the term “optionally substituted” isintended to mean that the group in question may be substituted one orseveral times, preferably 1-5 times, in particular 1-3 times) withgroup(s) selected from hydroxy (which when present in an enol system maybe represented in the tautomeric keto form), C₁₋₆-alkyl, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, oxo (which may be represented in the tautomeric enolform), carboxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl, formyl, aryl,aryloxy, arylamino, aryloxycarbonyl, arylcarbonyl, heteroaryl,heteroarylamino, amino, mono- and di(C₁₋₆-alkyl)amino; carbamoyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono-and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkylcarbonylamino, cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy,C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkyl-suphonyl, C₁₋₆-alkyl-sulphinyl,C₁₋₆-alkylsulphonyloxy, nitro, sulphanyl, amino, amino-sulfonyl, mono-and di(C₁₋₆-alkyl)amino-sulfonyl, dihalogen-C₁₋₄-alkyl,trihalogen-C₁₋₆-alkyl, halogen, where aryl and heteroaryl representingsubstituents may be substituted 1-3 times with C₁₋₄-alkyl, C₁₋₄-alkoxy,nitro, cyano, amino or halogen, and any alkyl, alkoxy, and the likerepresenting substituents may be substituted with hydroxy, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidine.

Preferably, the substituents are selected from hydroxy, C₁₋₆-alkyl,C₁₋₆-alkoxy, oxo (which may be represented in the tautomeric enol form),carboxy, C₁₋₆-alkylcarbonyl, formyl, amino, mono- anddi(C₁₋₆-alkyl)amino; carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino, guanidino,carbamido, C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkyl-suphonyl, C₁₋₆-alkyl-sulphinyl,C₁₋₆-alkylsulphonyloxy, sulphanyl, amino, amino-sulfonyl, mono- anddi(C₁₋₆-alkyl)amino-sulfonyl or halogen, where any alkyl, alkoxy and thelike representing substituents may be substituted with hydroxy,C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidine. Especially preferred examplesare C₁₋₆-alkyl, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino,sulphanyl, carboxy or halogen, where any alkyl, alkoxy and the likerepresenting substituents may be substituted with hydroxy, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidine.

In the present context the term “nitrogen-containing heterocyclic ring”is intended to mean heterocyclic ring or ring system in which at leastone nitrogen atom is present. Such a nitrogen is, with reference to theformula, carrying the substituents R₁ and R₂. The “nitrogen-containingheterocyclic ring” may further comprise additional heteroatoms, e.g.nitrogen (═N—or —N—), sulphur, and/or oxygen atoms. Examples of suchrings are aromatic rings such as pyridine, pyridazine, pyrimidine,pyrazine, triazine, thiophene, oxazole, isoxazole, thiazole,isothiazole, pyrrole, imidazole, pyrazole, tetrazole, quinoline,benzothiazole, benzotriazole, benzodiazole, benzoxozole, triazole,isoquinoline, indole, benzopyrazole, thiadiazole, and oxadiazole. Themost interesting examples of aromatic rings are pyridine, pyridazine,pyrimidine, pyrazine, thiophene, tetrazole, oxazole, isoxazole,thiazole, isothiazole, pyrrole, imidazole, pyrazole, quinoline,triazole, isoquinoline, and indole, in particular pyridine, thiophene,imidazole, quinoline, isoquinoline, indole, and tetrazole.

Other examples of such rings are non-aromatic rings such asimidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine,diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane,aziridine, azirine, azetidine, pyroline, tropane, oxazinane(morpholine), azepine, dihydroazepine, tetrahydroazepine, andhexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane,thiazinane, thiazepane, thiazocane, oxazetane, diazetane, andthiazetane. The most interesting examples of non-aromatic rings areimidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine,diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane,azetidine, tropane, oxazinane (morpholine), oxazolane, oxazepane,thiazolane, thiazinane, and thiazepane, in particular imidazolidine,piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane,pyrrolidine, piperidine, azepane, oxazinane (morpholine), andthiazinane.

In the present context, i.e. in connection with the term“nitrogen-containing heterocyclic ring”, the term “optionallysubstituted” is intended to mean that the group in question may besubstituted one or several times, preferably 1-5 times, in particular1-3 times) with group(s) selected from the same substituents as definedabove for “optionally substituted aryl”.

As is evident from the formulae defined herein and the definitionsassociated therewith, certain compounds of the present invention arechiral. Moreover, the presence of certain unsaturated or cyclicfragments or multiple stereogenic atoms provides for the existence ofdiastereomeric forms of some of the compounds. The invention is intendedto include all stereoisomers, including optical, isomers, and mixturesthereof, as well as pure, partially enriched, or, where relevant,racemic forms. In particular, many compounds of the invention may be inthe form of E- or Z-stereoisomers, or mixtures of such isomers. TheE-isomers are generally preferred.

It should furthermore be understood that the compounds defined hereininclude possible salts thereof, of which pharmaceutically acceptablesalts are of course especially relevant for the therapeuticapplications. Salts-include acid-addition salts and basic salts.Examples of acid addition salts are hydrochloride salts, fumarate,oxalate, etc. Examples of basic salts are salts where the (remaining)counter ion is selected from alkali metals, such as sodium andpotassium, alkaline earth metals, such as calcium salts, potassiumsalts, and ammonium ions (⁺N(R′)₄, where the R's independently designateoptionally substituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl,optionally substituted aryl, or optionally substituted heteroaryl).Pharmaceutically acceptable salts are, e.g., those described inRemington's—The Science and Practice of Pharmacy, 20th Ed. Alfonso R.Gennaro (Ed.), Lippincott, Williams & Wilkins; ISBN: 0683306472, 2000,and in Encyclopedia of Pharmaceutical Technology. However, generallypreferred salt forming agents for application in the present inventionare organic dicarboxylic acids such as oxalic, fumaric, and maleic acid,and the like.

Thus, chalcones with aminoalkoxy groups can be prepared in theirsalt-forms thereby making the compounds particularly useful forpharmaceutical formulations. The use of appropriate selected salt formcan be used to control the dissolution rate In vivo. Furthermore, thedifferent salt forms have different bulk-properties that is ofimportance for the manufacturing process.

Preparation of Compounds

The aminoalkoxy-functional chalcones defined herein may be produced bymethods known per se for the preparation of chalcones or methods thatare analogous to such methods. Examples of excellent methods forpreparing compounds of the 1,3-bis-aromatic-prop-2-enone or the1,3-bis-aromatic-prop-2-ynone types are given in the following. Furtherexamples of methods for the preparation of the compound used accordingto the present invention are described in WO 95/06628 and WO 93/17671and in the references cited therein.

Compounds of the general formula I in which V is —CH═CH— can be preparedby reacting a ketone (an acetophenone in the case where Ar¹ is phenyl)(Y¹)_(m)—Ar¹(X¹)—C(═O)—CH₃with an aldehyde (a benzaldehyde in the case where Ar² is phenyl)HCO—Ar²(X²)—(Y²)_(p)wherein Ar¹, Ar², X¹, X², Y¹, Y², m and p refer to the definitions givenelsewhere herein.

This reaction, which is a condensation reaction, is suitably carried outunder acid or base catalysed conditions. A review of such processes maybe found in Nielsen, A. T., Houlihahn, W. J., Org. React. 16, 1968, p1-444. In particular the method described by Wattanasin, S. and Murphy,S., Synthesis (1980) 647 has been found quite successful. The reactionmay suitably be carried out in protic organic solvents, such as loweralcohols (e.g. methanol, ethanol, or tert-butanol), or lower carboxylicacids (formic, glacial acetic, or propionic acid), or in aprotic organicsolvents such as ethers (e.g. tetrahydrofuran, dioxane, or diethylether), liquid amides (e.g. dimethylformamide orhexamethylphosphordiamide), dimethylsulfoxide, or hydrocarbons (e.g.toluene or benzene), or mixtures of such solvents. When carrying out thereaction under base catalysed conditions, the catalyst may be selectedfrom sodium, lithium, potassium, barium, calcium, magnesium, aluminum,ammonium, or quaternary ammonium hydroxides, lower alkoxides (e.g.methoxides, ethoxides, tert-butoxides), carbonates, borates, oxides,hydrides, or amides of lower secondary amines (e.g. diisopropyl amidesor methylphenyl amides). Primary aromatic amines such as aniline, freesecondary amines such as dimethyl amine, diethyl amine, piperidine, orpyrrolidine as well as basic ion exchange resins may also be used.

Acid catalysts may be selected from hydrogen chloride, hydrogen bromide,hydrogen iodide, sulfuric acid, sulfonic acids (such asparatoluenesulfonic or methanesulfonic acid), lower carboxylic acids(such as formic, acetic or propionic acid), lower halogenated carboxylicacids (such as trifluoroacetic acid), Lewis acids (such as BF₃, POCl₃,PCl₅, or FeCl₃), or acid ion exchange resins.

A drawback of the base catalysed condensation is the poor yield obtainedif the aromatic ring in which the ketone or the aldehyde or both issubstituted with one or more hydroxy groups. This drawback can beovercome by masking the phenolic group as described by T. Hidetsugu etal. in EP 0 370 461. Deprotection is easily performed by mineral acidssuch as hydrochloric acid.

The reaction is typically carried out at temperatures in the range of0-100° C., e.g. at room temperature. Reaction times are typically from30 min to 24 hours.

The starting materials for the synthesis (acetophenone andbenzaldehyde), may be obtained from commercial sources or may besynthesised according to well-known methods. Theaminoalkoxy-benzaldehydes and aminoalkoxy-acetophenones can besynthesized by alkylation of the corresponding hydroxy-benzaldehydes orhydroxy-acetophenones (FIG. 1). Alternatively the aminoalkoxy-chalconescan be prepared by alkylation of the corresponding hydroxy-chalcone.

Compounds of the general formula I in which V is —C≡C— may be preparedby reacting an activated derivative of a carboxylic acid of the generalformula(Y¹)_(m)—Ar¹(X¹)—COOHwith an ethyne derivativeH—C≡C—Ar²(X²)—(Y²)_(p)wherein Ar¹, Ar², X¹, X², Y¹, Y², m, and p refer to the definitionsgiven elsewhere herein.

Reactions of this type are described by Tohda, Y., Sonogashihara, K.,Haghara, N., Synthesis 1977, p 777-778. It is contemplated that theactivated derivative of the carboxylic acid may be an activated ester,an anhydride or, preferably, an acid halogenide, in particular the acidchloride. The reaction is normally carried out using the catalystsdescribed by Tohda, Y. et al. cited above, namelycopper(I)iodide/triphenylphosphine-palladium dichloride. The reaction issuitably carried out in triethylamine, a mixture of triethylamine andpyridine or triethylamine and toluene under a dry inert atmosphere suchas nitrogen or argon. The reaction is generally carried out at reducedtemperature such as in the range from −80° C. to room temperature, thereaction time typically being from 30 minutes to 6 hours.

In the above reactions; it may be preferred or necessary to protectvarious sensitive or reactive groups present in the starting materialsto prevent said groups from interfering with the reactions. Suchprotection may be carried out in a well-known manner, e.g. as describedin “Protective Groups in Organic Chemistry” by Wuts and Greene,Wiley-Interscience; ISBN: 0471160199; 3nd edition (May 15, 1999). Forexample, in the reaction between the activated acid derivative and theacetylene derivative, a hydroxy group on Ar¹ and/or Ar² may be protectedin the form of the methoxymethyl ether, N,N-dimethylcarbamoyl ester, orallyl ether. The protecting group may be removed after the reaction in amanner known per se.

The ethyne derivative may be prepared by standard methods, e.g. asdescribed by Nielsen, S. F. Et al., Bioorg. Med. Chem. 6, pp 937-945(1998). The carboxylic acids may likewise be prepared by standardprocedures, e.g. as described in the examples.

Compounds of the general formula I in which V is —CH₂—CH₂— can beprepared by ionic hydrogenation of the corresponding α,β-unsaturatedcompound where V is —CH═CH— as it has been described by the inventors inNielsen, S. F. et al. Tetrahedron, 53, pp 5573-5580 (1997).

Further possible synthetic routes for the preparation of the saturatedvariants are described in “Advanced Organic Chemistry” by Jerry March,3^(rd) ed. (especially chapter 15, pages 691-700) and references citedtherein. Thus, it is possible to obtain a large variety of compounds ofthe 1,3-bis-aromatic-propan-1-one type from the correspondingprop-2-en-1-ones.

Therapeutic Uses

The present inventors have found that that the novel compound haveinteresting properties as bacteriostatic, bacteriocidal andantiparasitic agents (see the Examples section). It is, of course,possible that the compounds also have other interesting properties to beutilised in the medical field.

Thus, the present invention provides, in,one aspect, a compound(chalcone derivative) as defined herein for use as a drug substance, i.e. a medicament.

Moreover, further aspects the invention relate to the use of thecompounds as defined herein for the preparation of a medicament for thetreatment of infections, such as infections associated with bacteria,protozoas or Leishmania spp.

The invention also provides, in still further aspects, methods for thetreatment of infections such as infections associated with bacteria,protozoa or Leishmania spp in a mammal, comprising the administration ofthe compounds as defined herein to said mammal.

In one aspect, the chalcone derivatives may be used for the treatment ofbacterial infections in a mammal in need thereof. Such bacterialinfections may be associated with common Gram-positive and/orGram-negative pathogenes or with microaerophilic or anaerobic bacteria.As a particularly relevant example of bacteria against which chalconederivatives demonstrates an effect can be mentioned antibiotic-sensitiveor -resistant strains of S.aureus and/or E.faecium. Other examplesinclude community acquired and nosocomial respiratory infections,including S.pneumoniae, S.pyogenes and members of Enterobacteriaceae(e.g. E.coli), microaerophilic bacteria associated with gastric disease(e.g. Helicobacter pylori) or pathogenic anaerobic bacteria (e.g.Bacteroides fragilis and Clostridium species).

According to the present invention, particularly relevant compounds fortreatment of such bacterial infections may be defined by the followingpreferred embodiments.

In one preferred embodiment Ar¹ and Ar² are both phenyl, m is 0, p is 1,and V is —CH═CH—. Further, the location of the group Y² is preferablythe 2-, 3- or 4-position, most suitably the 2-position. Additionalsubstituents defined by X² may typically be selected from the list,comprising alkyl, alkenyl, and optionally substituted phenyl. X²typically designates one substituent, preferably located in the5-position. Further preferred compounds of such embodiments includethose wherein X¹ represents 0-3, such as one, amino, hydroxy,alkylsulfonylamido, alkylamido, alkyl, or halo group located in the 2-,3-, or 4-position, and those wherein X¹ represents 0-3, such as one,dialkylaminomethyl group located In the2-, 3-, or 4-position, and thosewherein X¹ represents 0-3, such as one, dialkyaminomethyl group locatedin the 2-, or 3-position supplemented by a alkoxy or hydroxy group inthe 4- or 5-position, and those wherein X¹ represents 0-3, such as one,substituent of the formula —NR^(n)—B—N(R^(p))R^(q) located in the 2- or3-position.

Also preferred are compounds where Ar¹ and Ar² are both phenyl, m is 1,p is 1, and V is —CH═CH—. Further, the location of the group Y² ispreferably the 2-, 3- or 4-position, most suitably the 2-position. Thelocation of the Y¹ substituent is suitably the 2-, 3-, or 4-position.

In another preferred embodiment Ar¹ and Ar² are both phenyl, m is 0, pis 1, and V is —CH₂—CH₂—. Further, the location of the group Y² ispreferably the 2-, 3- or 4-position, most suitably the 2-position.Additional substituents defined by X² may typically be selected from thelist comprising alkyl, alkenyl, and optionally substituted phenyl. X²typically designates one substituent, preferably located in the5-position. Further preferred compounds of such embodiments includethose wherein X¹ represents 0-3, such as one, amino, hydroxy,alkylsulfonylamido, alkylamido, alkyl, or halo group located in the 2-,3-, or 4-position, and those wherein X¹ represents 0-3, such as one,dialkylaminomethyl group located in the 2-, 3-, or 4-position, and thosewherein X¹ represents 0-3, such as one, dialkyaminomethyl group locatedin the 2- or 3-position supplemented by a hydroxy group in the 4-, or5-position, and those wherein X¹ represents 0-3, such as one,substituent of the formula —NR^(n)—B—N(R^(p))R^(q) located in the 2- or3-position.

Also preferred are compounds where Ar¹ and Ar² are both phenyl, m is 1,p is 1, and V is —CH₂—CH₂—. Further, the location of the group Y² ispreferably the 2-, 3- or 4-position, most suitably the 2-position. Thelocation of the Y¹ substituent is suitably the 2-, 3-, or 4-position.

Additionaly, compounds wherein Ar¹ and Ar² are both phenyl, m is 1, p is0, and V is —CH═CH—are interesting, especially when Y¹ is located in the2-, 3-, or 4-position; and X² represents 2- and/or 4-substitution,suitably halo.

In still another aspect, the chalcone derivatives as provided herein canbe used for the treatment of infections associated with protozoa in amammal. Examples of infections are those caused by a protozoa selectedfrom Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale andPlasmodium malariae.

In a still further aspect, the chalcone derivatives as defined hereincan be used for the treatment of infections in a mammal associated withLeishmania spp. Such infections may be cutaneous and/or visceral.

Preliminary results have shown that compounds wherein the Y² is theaminoalkoxy-substituent positioned in the 2 position where Ar¹ isphenyl, are particularly promising for the treatment of infectionscaused by Plasmodium. Those in which X² represents at least onesubstituent selected from C₁₋₆-alkyl, hydroxy, C₁₋₆-alkoxy,C₁₋₆-alkylcarbonyl, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted arylamino, optionally substitutedheteroaryl, optionally substituted heteroarylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkyl-carbonylamino, optionally substitutedC₁₋₆-alkylthio, optionally substituted heterocyclyl, optionallysubstituted heterocyclyloxy, optionally substituted heterocyclylaminoand halogen, in particular from C₁₋₆-alkyl, optionally substitutedphenyl, and hydroxy, e.g. from C₁₋₆-alkyl and optionally substitutedphenyl, appear to be particularly promising. Particular examples ofefficient chalcone derivatives are those where X¹ represents at leastone substituent, one of which being located in the 2- or 3-position ofthe phenyl ring, and preferably being selected from amino-C₁₋₆-alkyl andmono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl, or those where X¹ representsat least one substituent, one of which being located in the 4-positionof the phenyl ring, and preferably being selected from hydroxy,amino-C₁₋₆-alkylamino and mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkylamino.

One particularly suitable embodiment for such application is the onewherein Ar¹ and Ar² are both phenyl, m is 0, p is 1, and V is —CH═CH—.Further preferred among such compounds are the ones wherein Y² islocated in the 2-position, and designates a group of formula—O—(CH₂)₂₋₃—N(R¹)R², wherein R¹ and R² are independently alkyl orN-containing heterocyclic ring, such as methyl, ethyl, t-butyl,pyrrolidine; and the like. Also preferred are compounds whichadditionally carry a substituent as defined by X², suitably located inthe 5-position, and selected from alkyl and optionally substituted aryl,such as optionally substituted phenyl. In such embodiments, substituentsdefined by X¹, if present, may typically be selected so that X¹ isdialkylaminomethyl located in the 2-, or 3-position, optionallysupplemented by methoxy or hydroxy groups in the 4- and/or 5-positions,or selected so that X¹ represents 1-3 halo, alkoxy or hydroxysubstituents located in the 2-, 3-, or 4-positions, such as2,3-dihalo-4-hydroxy, 4-halo, 2-halo-3-hydroxy, 2-butoxy, and the like,or selected so that X¹ represents a group of the formula—NR^(n)—B—N(R^(p))R^(q), preferably 2- or 3-(4-alkylpiperazin-1-yl), 3-or 4-((2-(dialkylamino)ethyl)amino), or2-((2-(dialkylamino)ethyl)methylamino).

Another particularly suitable embodiment such for application is the onewherein Ar¹ and Ar² are both phenyl, m is 0, p is 1, and V is —CH═CH—,and Y² is located in the 3-position, and designates a group of formula—O—(CH₂)₂₋₃—N(R¹)R², wherein R¹ and R² are independently alkyl. Amongsuch compounds, X¹ may typically be a dialkylaminomethyl substituent,such as dimethylaminomethyl, suitably located in the 2-position.

Also interesting for such application are compounds wherein Ar¹ and Ar²are both phenyl, m is 1, p is 1, and V is —CH═CH—. Among such compounds,preferred meanings of Y¹ and Y² include —O—(CH₂)₂₋₃—N(R¹)R², wherein R¹and R² are independently alkyl, such as methyl. Suitable selections ofX¹ and X², if present, are halo, particularly 2-halo, such as 2-fluoro,and aryl, particularly optionally substituted 5-phenyl.

Other preliminary results have shown that compounds wherein the Y² isthe aminoalkoxy-substituent positioned in the 2 position where Ar¹ isphenyl, are particularly promising for the treatment of infectionscaused by Leishmania spp. Those in which X² represents at least onesubstituent selected from C₁₋₆-alkyl, hydroxy, C₁₋₆-alkoxy,C₁₋₆-alkylcarbonyl, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted arylamino, optionally substitutedheteroaryl, optionally substituted heteroarylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino, optionally substitutedC₁₋₆-alkylthio, optionally substituted heterocyclyl, optionallysubstituted heterocyclyloxy, optionally substituted heterocylylamino andhalogen, in particular from C₁₋₆-alkyl, optionally substituted phenyl,and hydroxy, e.g. from C₁₋₆-alkyl and optionally substituted phenyl,appear to be particularly promising.

Particularly suitable embodiments for such application include thosewherein Ar¹ and Ar² are both phenyl, the sum of m and p is 1, and V is—CH═CH—. Typically, in such compounds, n is 2-6, such as 2 or 3, and thelocation of Y¹ or Y² is in the 2-, 3-, or 4-position, with the2-position being especially preferred. Further, in such embodimentswhere m is 1, Y¹ may typically be supplemented with additional groupsX², suitably selected from non-charged substituents such as alkyl,alkoxy and halo, and located in the 2-, 3-, or 4-positions. Inembodiments where p is 1, Y² may typically be supplemented by additionalsubstituents, X², suitably selected from non-charged, bulky groups suchas alkyl and aryl and/or by substituents defined by X¹, suitablyselected from non-charged groups such as alkyl, alkoxy and halo.Further, generally interesting embodiments are those where X¹ designatesa dialkylaminomethyl group, suitably located in the 2-position.

Still other preliminary results indicate that compounds wherein the Y²is the aminoalkoxy-substituent positioned in the 2 position where Ar¹ isphenyl, are particularly promising for the treatment of infectionscaused by S. aureus. Those in which X² represents at least onesubstituent selected from C₁₋₆-alkyl, hydroxy, C₁₋₆-alkoxy,C₁₋₆-alkylcarbonyl, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted arylamino, optionally substitutedheteroaryl, optionally substituted heteroarylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino, optionally substitutedC₁₋₆-alkylthio, optionally substituted heterocyclyl, optionallysubstituted heterocyclyloxy, optionally substituted heterocyclylaminoand halogen, in particular from C₁₋₆-alkyl, optionally substitutedphenyl, and hydroxy; e.g. from C₁₋₆-alkyl and optionally substitutedphenyl, appear to be particularly promising.

Formulation of Pharmaceutical Compositions

The chalcone derivatives are typically formulated in a pharmaceuticalcomposition prior to use as a drug substance.

The administration route of the compounds (aminoalkoxy-functionalchalcones) as defined herein may be any suitable route that leads to aconcentration in the blood or tissue corresponding to a therapeuticconcentration. Thus, e.g., the following administration routes may beapplicable although the invention is not limited thereto: the oralroute, the parenteral route, the cutaneous route, the nasal route, therectal route, the vaginal route and the ocular route. It should be clearto a person skilled in the art that the administration route isdependant on the particular compound in question, particularly, thechoice of administration route depends on the physico-chemicalproperties of the compound together with the age and weight of thepatient and on the particular disease or condition and the severity ofthe same.

The compounds as defined herein may be contained in any appropriateamount in a pharmaceutical composition, and are generally contained inan amount of about 1-95% by weight of the total weight of thecomposition. The composition may be presented in a dosage form which issuitable for the oral, parenteral, rectal, cutaneous, nasal, vaginaland/or ocular administration route. Thus, the composition may be in formof, e.g., tablets, capsules, pills, powders, granulates, suspensions,emulsions, solutions, gels including hydrogels, pastes, ointments,creams, plasters, drenches, delivery devices, suppositories, enemas,injectables, implants, sprays, aerosols and in other suitable form.

The pharmaceutical compositions may be formulated according toconventional pharmaceutical practice, see, e.g., “Remington'sPharmaceutical Sciences” and “Encyclopedia of PharmaceuticalTechnology”, edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker,Inc., New York, 1988. Typically, the compounds defined herein areformulated with (at least) a pharmaceutically acceptable carrier orexipient. Pharmaceutically acceptable carriers or exipients are thoseknown by the person skilled in the art.

Thus, the present invention provides a pharmaceutical compositioncomprising a compound as defined herein in combination with apharmaceutically acceptable carrier.

Pharmaceutical compositions according to the present invention may beformulated to release the active compound substantially immediately uponadministration or at any substantially predetermined time or time periodafter administration. The latter type of compositions are generallyknown as controlled release formulations.

In the present context, the term “controlled release formulation”embraces i) formulations which create a substantially constantconcentration of the drug within the body over an extended period oftime, ii) formulations which after a predetermined lag time create asubstantially constant concentration of the drug within the body over anextended period of time, iii) formulations which sustain drug actionduring a predetermined time period by maintaining a relatively,constant, effective drug level in the body with concomitant minimizationof undesirable side effects associated with fluctuations in the plasmalevel of the active drug substance (sawtooth kinetic pattern), iv)formulations which attempt to localize drug action by, e.g., spatial,placement of a controlled release composition adjacent to or in thediseased tissue or organ, v) formulations which attempt to target drugaction by using carriers or chemical derivatives to deliver the drug toa particular target cell type.

Controlled release formulations may also be denoted “sustained release”,“prolonged release”, “programmed release”, “time release”,“rate-controlled” and/or “targeted release” formulations.

Controlled release pharmaceutical compositions may be presented in anysuitable dosage forms, especially in dosage forms intended for oral,parenteral, cutaneous nasal, rectal, vaginal and/or ocularadministration. Examples include single or multiple unit tablet orcapsule compositions, oil solutions, suspensions, emulsions,microcapsules, microspheres, nanoparticles, liposomes, delivery devicessuch as those intended for oral, parenteral, cutaneous, nasal, vaginalor ocular use.

Preparation of solid dosage forms for oral use, controlled release oraldosage forms, fluid liquid compositions, parenteral compositions,controlled release parenteral compositions, rectal compositions, nasalcompositions, percutaneous and topical compositions, controlled releasepercutaneous and topical compositions, and compositions foradministration to the eye can be performed essentially as described inthe applicant's earlier International application No. WO 99/00114, page29, line 9, to page 40, line 3. Also, and more generally, theformulation and preparation of the above-mentioned compositions arewell-known to those skilled in the art of pharmaceutical formulation.Specific formulations can be found in “Remington's PharmaceuticalSciences”.

Dosages

The compound are preferably administered in an amount of about 0.1-50 mgper kg body weight per day, such as about 0.5-25 mg per kg body weightper day.

For compositions adapted for oral administration for systemic use, thedosage is normally 2 mg to 1 g per dose administered 1-4 times daily for1 week to 12 months depending on the disease to be treated.

The dosage for oral administration for the treatment of parasiticdiseases is normally 1 mg to 1 g per dose administered 1-2 times dailyfor 1-4 weeks, in particular the treatment of malaria is to be continuedfor 1-2 weeks whereas the treatment of leishmaniasis will normally becarried out for 3-4 weeks.

The dosage for oral administration for the treatment of bacterialdiseases is normally 1 mg to 1 g per dose administered 1-4 times dailyfor 1 week to 12 months; in particular, the treatment of tuberculosiswill normally be carried out for 6-12 months.

The dosage for oral administration of the composition in order toprevent diseases is normally 1 mg to 75 mg per kg body weight per day.The dosage may be administered once or twice daily for a period starting1 week before the exposure to the disease until 4 weeks after theexposure.

For compositions adapted for rectal use for preventing diseases, asomewhat higher amount of the compound is usually preferred, i.e. fromapproximately 1 mg to 100 mg per kg body weight per day.

For parenteral administration, a dose of about 0.1 mg to about 50 mg perkg body weight per day is convenient. For intravenous administration adose of about 0.1 mg to about 20 mg per kg body weight per dayadministered for 1 day to 3 months is convenient. For intraarticularadministration a dose of about 0.1 mg to about 20 mg per kg body weightper day is usually preferable. For parenteral administration in general,a solution in an aqueous medium of 0.5-2% or more of the activeingredients may be employed.

For topical administration on the skin, a dose of about 1 mg to about 5g administered 1-10 times daily for 1 week to 12 months is usuallypreferable.

In many cases, it will be preferred to administer the compound definedherein together with another antiparasitic, antimycotic or antibioticdrug, thereby reducing the risk of development of resistance against theconventional drugs, and reducing the amount of each of the drugs to beadministered, thus reducing the risk of side effects caused by theconventional drugs. Important aspects of this is the use of the compoundagainst Leishmania, where the compound is combined with anotherantileishmanial drug, or the antimalarial use of the compound where thecompound is used together with another antimalarial drug.

Method of Prediction

In a separate aspect, the present invention also provides a method ofpredicting whether a chemical compound has a potential inhibitory effectagainst a microorganism selected from Helicobacter pylori and Plasmodiumfalciparum, said method comprising preparing a mixture of adihydroorotate dehydrogenase, a substrate for dihydroorotatedehydrogenase and the chemcial compound, measuring the enzymaticactivity of dihydroorotate dehydrogenase (A), comparing the enzymaticactivity of dihydroorotate dehydrogenase (A) with the standard activityof dihydroorotate dehydrogenase (B) corresponding to the activity of adihydroorotate dehydrogenase in a similar sample, but without thechemical compound, predicting that the chemical compound has a potentialinhibitory effect against Helicobacter pylori and Plasmodium falciparumif A is significantly lower than B.

The method can be performed as described under DHODH Assay in theExamples section. It should be noted that the method is not onlyapplicable for the chalcone derivatives defined herein, but can begenerally applied to predict the potential inhibitory effect of anycompound. Preferably, however, the chemical compound is a chalconederivative, e.g. a chalcone derivative as defined herein.

EXAMPLES Preparation of Compounds

Chemical names presented below were generated using the softwareChemDraw Ultra, version 6.0.1, from CambridgeSoft.com.

The general method for the preparation of the A ring or B ring havingthe aminoalkoxy-functional group is illustrated in FIG. 1.

Characterisation of the Compounds

The compounds were characterised by NMR (300 MHz) and GC-MS or LC-MS.The purity of the chalcone derivatives was >95% determined by HPLC.

General Procedure A

Preparation of alkyl- or dialkyl aminomethyl acetophenones

To a solution of (2-methyl-[1,3]dioxan-2-yl) benzaldehyde (165 mmol) andamine (247 mmol) in dry THF (1.5 L) was added sodiumtriacetoxyborohydride (257 mmol) under argon. The resulting suspensionwas stirred at room temperature for 18 hr. A solution of sodiumhydroxide (2M) was added and stirring was continued for approximately 30min, before the mixture was acidified using HCl (6M). The mixture wasstirred for 1 hr. and extracted with diethyl ether, which was discarded.The pH of the aqueous phase was adjusted to 11-14 using sodium hydroxideand extracted again with diethyl ether. The latter organic phase, wasdried (Na₂SO₄), filtered and evaporated to give the title products,which were used without further purification.

General Procedure B

Preparation of Amino Acetophenones

3′- or 4′-bromoacetophenone ketal (40 mmol), amine (48 mmol), Pd₂(dba)₃(0.2 mmol, 1 mol % Pd), rac-BINAP (0.6 mmol) and Na-t-OBu (68 mmol) wasstirred in degassed toluene (60 mL) at 80° C. for 18 h. The darkbrownmixture was poured into ice cold hydrochloric acid (1M, 200 mL) andstirred vigorously for 2 hours at 25° C. The solution was cooled to 0°C. and pH was adjusted to 13 using 6M NaOH(aq) and extracted with Et₂O(4×100 mL). The organic phase was dried (K₂CO₃) and the solvent wasremoved under reduced pressure. The resulting crude oil purified byflash chromatography using 5% Et₃N in EtOAc.

General Procedure C

Preparation of (2-dimethylaminoethoxy)-acetophenones

A solution of hydroxy acetophenone (48 mmol), 2-(dimethylamino)ethylchloride, HCl (96 mmol) and K₂CO₃ (48 mmol) in dry DMF (300 mL) wasrefluxed overnight. The reaction was cooled to room temperature andadded 2 M NH₃ solution (aq) (600 mL) and extracted with diethyl ether.The combined organic phases were dried (Na₂SO4) and evaporated in vacuo.The residue purified by column chromatography gave the title compound.

General Procedure D

Preparation of (3-dimethylaminopropoxy)-acetophenones

A solution of hydroxy acetophenone (48 mmol), 3-(dimethylamino)propylchloride, HCl (96 mmol) and 60% NaH (48 mmol) in dry DMF (300 mL) washeated to 100° C. for 3 h. The reaction was cooled to room temperatureand added 2 M NH₃ solution (aq) (600 mL) and extracted with CH₂Cl₂(3×200 mL). The combined organic phases were dried (Na₂SO₄) andevaporated in vacuo. The resulting yellow solution was redissolved inwater (500 mL) and extracted with diethyl ether. The combined organicphases were dried (Na₂SO₄) and evaporated in vacuo. The residue purifiedby column chromatography gave the title compound.

General Procedure E

Preparation of (2-dimethylaminoethoxy)-benzaldehydes

A stirred solution of hydroxybenzaldehyde (59.7 mmol) in dry toluene(200 mL) and DMSO (1 mL) was added 60% NaH (60 mmol) under ice cooling.The reaction was slowly heated to room temperature.2-(dimethylamino)ethyl chloride, HCl (110 mmol) dissolved in water (50mL) was added NaOH (110 mmol) and the aqueous phase was extracted withtoluene (3×30 mL). The combined organic phases were dried (Na₂SO₄) andslowly added to the reaction. The solution was heated to 90° C. for 16h. The reaction mixture was cooled to room temperature and washed withwater (3×100 mL), 2N NaOH (100 mL) and dried (Na₂SO₄). Evaporation invacuo gave the title products.

General Procedure F

Preparation of (3-dimethylaminopropoxy)-benzaldehydes/or -biarylcarbaldehydes

A stirred solution of hydroxybenzaldehyde/hydroxy biaryl carbaledehyde(59.7 mmol) in dry toluene (200 mL) and DMSO (1 mL) was added 60% NaH(60 mmol) under ice cooling. The reaction was slowly heated to roomtemperature. 3-Dimethylaminopropylchloride, HCl (110 mmol) dissolved inwater (50 mL) was added NaOH (110 mmol) and the aqueous phase wasextracted with toluene (3×30 mL). The combined organic phases were dried(Na₂SO₄) and slowly added to the reaction. The solution was heated to90° C. for 16 h. The reaction mixture was cooled to room temperature andwashed with water (3×100 mL), 2N NaOH (100 mL) and dried (Na₂SO₄).Evaporation in vacuo gave the title products.

General Procedure G

Preparation of Biaryl Carbaldehydes

A solution of Na2CO3 (44 mmol) in water, (20 mL) was added to a solutionof bromobenzaldehyde (14.7 mmol) and (hetero)arylboronic acid (17.6mmol) in DME (40 mL). The mixture was flushed with argon for 2 minutesfollowed by addition of Pd(PPh₃)₂Cl₂ (310 mg, 3 mol %). The reaction washeated at reflux and left overnight under an atmosphere of argon. Thereaction was cooled, 2M Na₂CO₃ was added, and the mixture was extractedwith EtOAc (3×20 mL). The title products were purified by flashchromatography.

General Procedure H

Synthesis of Chalcones

To a solution of an acetophenone (2 mmol) and a benzaldehyde (2 mmol) in96% EtOH (10 mL) was added 8M NaOH (0.3 mL), and the mixture was stirredfor 3-18 hours at 25° C. The mixture was evaporated on Celite® and theproduct was isolated by flash chromatography. The aminochalcone wasdissolved in MeOH:Et₂O (1:9 v/v, 10 mL) and a solution of fumaric acidor oxalic acid in MeOH:Et₂O (1:9 v/v) was added. The salt was filteredoff and recrystallised from MeOH or MeCN. Alternatively, theaminochalcone was dissolved in EtOH before 3M HCl in EtOH was added atroom temperature. The salt was filtered off. Some aminochalcones did notundergo salt formation, and was isolated as the free base.

General Procedure I

Preparation of (2-dimethylaminoethoxy)-chalcones

A solution of hydroxy chalcone (3.5 mmol), 2-(dimethylamino)ethylchloride, HCl (3.5 mmol) and K₂CO₃ (10.5 mmol) in dry DMF (20 mL) washeated to reflux for 3 h. The reaction was cooled to room temperatureand added 2 M NH₃ solution (aq) and extracted with ether. The combinedorganic phases were dried (Na₂SO₄) and evaporated in vacuo. The residuepurified by column chromatography gave the title compound.

General Procedure J

Formylation of 2-(biphenyl-4-yloxy)-ethyl]-dimethyl-amine

A solution of TiCl₄ in CH₂Cl₂ (3 M, 149 mmol) was added under argon at0° C. to a solution of 1,1-dichloro methyl methyl ether (10 mL) and2-(biphenyl-4-yloxy)-ethyl]-dimethyl-amine (13.5 mmol) in CH₂Cl₂.Allowed to warm to RT during 3 hours. Poured onto ice and the pH wasadjusted to basic pH using 2M NaOH. The phases were separated and theaqueous phase was extracted with CH₂Cl₂. The combined organic phaseswere dried (Na₂SO₄) and evaporated to give the pure title products.

General Procedure K

Synthesis of Amines from Alkyl Halides

A solution of halide (4.5 mmol), amine (22.5 mmol) and sodium iodide(13.5 mmol) in DMF (50 mL) and water (5 mL) was heated at 95° C.overnight. The reaction was cooled and added water and extracted withether (3×100 mL). The collected organic phases were evaporated in vacuoand redissolved in EtOAc (50 mL). The solution was added 2M HCl (50 mL)and stirred for 2 hours at room temperature. Addition of 2N NaOH toneutral pH and separation of the organic and aqueous phase gave yellowoil that was purified by flash chromatography.

General Procedure L

Alkylation of Phenols with Alkyl Dihalides

A solution of phenol (20.3 mmol) and alkyl dihalide (100 mmol) in THF(100 mL) and 2M NaOH aq (50 mL) was left overnight at 70 C undervigorous stirring. The reaction was cooled and added water and extractedwith ether (3×100 mL). The title products were purified by flashchromatography.

General Procedure M

Preparation of 2-(biphenyl-4-yloxy)-ethyl]-dimethyl-amine

A solution of biphenyl-4-ol (18 mmol), 2-(dimethylamino)ethyl chloride,HCl (27 mmol) and K₂CO₃ (54 mmol) in acetone (200 mL) was refluxedovernight. The reaction was cooled to room temperature, poured intowater, and extracted with ethyl acetate. The combined organic phaseswere dried (Na₂SO₄) and evaporated in vacuo. The residue was usedwithout further purification.

General Procedure N

Reduction of Chalcones

Triethylsilane (0.150 mol) was added to a solution of 3,1-diphenylpropenone (0.0075 mol) in trifluoro acetic acid. Stirred at 25° C. for30 hours, before the solution was poured into ice-cold NaOH (2M, 150mL). Extracted with EtOAc, dried over Na₂SO₄, filtered and evaporated onCelite®. Purified by flash chromatography (EtoAc/heptane, 3% Et₃N). Theresulting oil was dissolved in MeOH:Et₂O (1:9 v/v, 10 mL) and a solutionof fumaric acid in MeOH:Et₂O (1:9 v/v) was added. Some propanones didnot undergo salt formation, and was isolated as the free base. Thepurity was >95% determined by HPLC and the molecular weight wasdetermined by LC-MS.

General Procedure O

Nucleophilic Aromatic Substitution on Fluoroacetophenone

A mixture of fluoroacetophenone (40, mmol), amine (50 mmol), K₂CO₃ (50mmol) was refluxed in dry DMF (20 mL) under an argon atmosphere for 18h. The DMF was removed using an oilpump and water (50 mL) was added tothe residue. The water phase was extracted with Et₂O (2×100 mL) and theorganic phase was dried (K₂CO₃) and evaporated to yellow oil, which waspure enough for further reaction.

Acetophenones

1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-ethanone

General procedure A gave the title compound as a brown oil in 78% yleld.¹H-NMR (CDCl₃) δ 7.42-7.29 (m, 4H), 3.65 (s, 2H), 2.54 (s, 3H), 2.43 (b,8H), 2.27 (s, 3H).

1-(2-{[(2-Dimethylamino ethyl)-methyl-amino]-methyl}-phenyl)-ethanone

General procedure A gave the title compound as brown oil in. 88% yleld.¹H-NMR (DMSO-d₆) δ 7.51 (d, 1H), 7.40-7.30 (m, 3H), 3.57 (s, 2H), 2.56(s, 3H), 2.39-2.32 (m, 2H), 2.29-2.23 (m, 2H), 2.07 (s, 6H), 2.03 (s,3H).

1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl}-ethanone

General procedure A gave the title compound as brown oil in 44% yleld.¹H-NMR (DMSO-d₆) δ

7.52 (dd, 1H), 7.51 (dd, 1H), 7.40 (td, 1H), 7.30 (td, 1H), 3.63 (s,2H), 2.48 (s, 3H), 1.91 (x, 3H), 1.03 (s, 9H).

1-[2-(4-Hydroxy-piperidin-1-ylmethyl)-phenyl]-ethanone

General procedure A gave the title, compound as brown oil in 82% yleld.¹H-NMR (CDCl₃) δ 7.32 (dt, 1H), 7.28-7.19 (m, 3H), 3.65-3.56 (m, 1H),3.54 (s, 2H), 2.63-2.55 (m, 2H), 2.45 (s, 3H), 2.10-2.01 (m, 2H),1.79-1.70 (m, 2H), 1.49-1.36 (m, 2H).

1-(2-Morpholin-4-ylmethyl-phenyl)-ethanone

General procedure A gave the title compound as yellow oil in 89% yield.Pure according to GCMS m/z: 219.

1-(3-Dimethylaminomethyl-4-methoxy-phenyl)-ethanone

(5-Bromo-2-methoxy-benzyl)-dimethyl-amine (29 mmol), Butoxy-ethene (100mmol), Palladium acetate (0.9 mmol), 1,3-Bis(diphenylphosphino)propane(1.8 mmol), and potassium carbonate were suspended in DMF (50 ml) andH₂O under argon. Heated at 80° C. overnight. Poured into hydrochloricacid (2 M) and stirred for 1 hour. The mixture was adjusted to basic pHand extracted with CH₂Cl₂. The organic phase was evaporated on celiteand the residue was purified by flash chromatography to give the titleproduct as orange oil in 42% yield. ¹H-NMR (CDCl₃) δ 7.90 (s, 1H), 7.88(dd, 1H), 6.89 (d, 1H), 3.88 (s, 3H), 3.44 (s, 2H), 2.55 (s, 3H), 2.25(s, 6H).

1-[4-Hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone

A solution of formaldehyde (37% w/w, 8.2 mL) was added to a solution of4′-Hydroxy acetophenone (100 mmol), and N-methylpiperazine (110 mmol) inEtOH. Heated at reflux overnight. The solvent was evaporated on celiteand the residue was purified by flash chromatography and crystallizedfrom heptane to give the title product as white needles in 55% yield.¹H-NMR (DMSO-d₆) δ 7.76 (dd, 1H), 7.74 (s, 1H), 6.81 (d, 1H), 3.69 (s,2H), 2.47 (br, 4H), 2.46 (s, 3H), 2.35 (br, 4H), 2.17 (s, 3H).

1-(2-Pyrrolidin-1-ylmethyl-phenyl)-ethanone

General procedure A gave the title product as colourless oil in 55%yield. ¹H-NMR (DMSO-d₆) δ 7.49 (d, 1H), 7.40 (dd, 2H), 7.34-7.29 (m,1H), 3.71 (s, 2H), 2.44 (s, 3H), 2.39-2.33 (m, 4H), 1.67-1.63 (m, 4H).

1-(3-Dimethylaminomethyl-phenyl)-ethanone

General procedure A gave the title product as yellow oil in 89% yield.¹H-NMR (CDCl₃) δ 7.89 (s, 1H), 7.85 (d, 1H), 7.52 (d, 1H), 7.42 (t, 1H),3.47 (s, 2H), 2.61 (s, 3H), 2.25 (s, 6H).

1-[4-(2-Dimethylamino-ethylamino)-phenyl]-ethanone

General procedure B gave the title product as brown oil in 86% yield.¹H-NMR (CDCl₃) δ 7.76 (d, 2H), 6.50 (d, 2H), 4.90 (bs, 1H), 3.13 (q,2H), 2.50 (t, 2H), 2.43 (s, 3H), 2.19 (s, 6H).

1-[3-(2-Dimethylamino-ethoxy)-phenyl]-ethanone

General procedure C gave the title product as brown oil in 26% yield.¹H-NMR (CDCl₃) δ 7.45-7.39 (m, 2H), 7.26 (t, 1H), 7.03 (ddd, 1H),4.04.(t; 2H), 2.69 (t, 2H), 2.49 (s, 3H), 2.28 (s, 9H).

1-[2-Fluoro-4-(tetrahydro-pyran-2-yloxy)-phenyl]-ethanone

A solution of 1-(2-fluoro-4-hydroxy-phenyl)-ethanone (130 mmol),3,4-dihydro-2H-pyran (260 mmol) and a catalytic amount of pyridiniump-toluenesulfonate in CH₂Cl₂ (200 mL) was left overnight at roomtemperature. The organic phase was washed with 1 N NaOH (aq) (1×50 mL)and dried (K₂CO₃). Evaporation in vacuo gave a brown oil, that waspurified by vacuum distillation. The desired product was isolated asclear oil in 74% yield: bp: 130-140 ° C./0.05 mbar. ¹H-NMR (CDCl₃) δ7.86 (t, 1H), 6.87 (dd, 1H), 6.82 (dd, 1H), 5.49 (t, 1H), 3.86-3.78 (m,1H), 3.67-3.61 (m, 1H), 2.59 (d, 3H), 1.97-1.60 (m, 6H).

1-[2-(4-Methyl-piperazin-1-yl)-4-(tetrahydro-pyran-2-yloxy)-phenyl]-ethanone

General procedure O gave the title compound as an yellow oil in 66%yield. ¹H-NMR (CDCl₃) δ 7.36 (d, 1H), 6.72-6.67 (m, 2H), 5.55 (t, 1H),3.75-3.71 (m, 1H), 3.59-3.55 (m, 1H), 2.91 (t, 4H), 2.54 (s, 3H),2.53-2.45 (m, 4H), 2.23 (s, 3H), 1.85-1.53 (m, 6H).

1-[3-(2-Dimethylamino-ethylamino)-phenyl]ethanone

General procedure B gave the title compound as yellow oil in 73% yield.¹H-NMR (CDCl₃) δ 7.28-7.18 (m, 3H), 6.85-6.78 (m, 1H), 4.45 (s, br, 1H),4.10-3.23 (m, 2H), 2.59-2.52 (m, 5H), 2.25 (s, 6H).

1-[2-(2-Dimethylamino-ethylamino)-phenyl]ethanone

General procedure O gave the title compound as yellow oil in 58% yield.

1-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-phenyl}ethanone

General procedure O gave the title compound as yellow oil in 93% yield.¹H-NMR (CDCl₃) δ 7.42-7.32 (m, 2H), 7.07 (d, 1H), 7.70-6.93 (td, 1H),3.17 (t, 2H), 2.80 (s, 3H), 2.61 (s, 3H), 2.49-2.42 (m, 2H), 2.20 (s,6H).

N-(3-Acetyl-phenyl)-2-dimethylamino-acetamide

A solution of 3′-amino-acetophenone (25 mmol) in THF (100 mL) was addedchloroacyl chloride (30 mmol). The mixture was stirred for 30 min,poured into ice cold 2M NaOH (aq) and extracted with Et₂O. The organicphase was dried and the solvent was removed under reduced pressuregiving the pure product. A solution of the product (10 mmol) andtriethyl amine (30 mmol) in ethanol was added amine (20 mmol) and themixture was refluxed for 4 hours. Ethanol was removed under reducedpressure and the product was dissolved in EtOAc and washed with 2M NaOH(aq). EtOAc was removed under reduced pressure giving the product aspure brown oil in 85% yield. ¹H-NMR (CDCl₃) 5 9.31 (s, 1H), 8.05 (m,2H), 7.72 (dt,1H), 7.46 (t, 1H), 3.11 (s, 2H), 2.62 (s, 3H), 2.41(s,.6H).

1-[4-(2-Dimethylamino-ethoxy)-2,fluoro-phenyl]-ethanone

General procedure C gave the title compound as a brown oil in 14% yield.¹H-NMR (CDCl₃) δ 7.88 (t, 1H), 6.77 (dd, 1H), 6.64 (dd, 1H), 4.12 (t,2H), 2.77 (t, 2H), 2.60 (d, 3H), 2.35 (s, 6H).

1-[4-(2-Dimethylaminoethoxy)-2-(4-methyl-piperazin-1-yl)-phenyl]-ethanone

General procedure O gave the title compound as an yellow oil in 17%yield. ¹H-NMR (CDCl₃) δ 7.49 (d, 1H), 6.60 (d, 1H), 6.56 (dd, 1H), 4.08(t, 2H), 3.02 (t, 4H), 2.73 (t, 2H), 2.62 (s, 3H), 2.35 (s, 3H), 2.34(s, 6H).

Benzaldehydes

4-Hydroxy-2′-methyl-biphenyl-3-carbaldehyde

General procedure G gave the title compound as brown crystals in 61%yield. ¹H-NMR (CDCl₃) δ 11.04 (s, 1H), 9.95 (d, 1H), 7.54-7.52 (m, 2H),7.32-7.24 (m, 5H), 7.07 (dd, 1H), 2.30 (s, 3H).

3-[1,3]Dioxan-2-yl-2′-methyl-biphenyl-4-ol

A solution of 4-hydroxy-2′-methyl-biphenyl-3-carbaldehyde (18.8 mmol) intoluene (100 mL) was added 1,3-dihydroxypropane (65.7 mmol) andp-toluenesulfonic acid (cat) and heated at reflux overnight in aDean-Stark set-up. The reaction was cooled and washed with a solution ofNa₂CO₃ (aq, 1 M). Evaporation in vacuo gave the title product as brownoil in 89% yield. ¹H-NMR (CDCl₃) δ 9.61 (bs, 1H), 7.34-7.10 (m, 6H),6.87 (d, 1H), 5.77 (s,1H), 4.13-4.07 (m, 2H), 3.95-3.86 (m, 2H), 2.20(s, 3H), 2.18-1.96 (m, 1H), 1.40 (d, 1H).

2-[4-(2-Chloro-ethoxy)-2′-methyl-biphenyl-3-yl]-[1,3]dioxane

General procedure L gave the title compound as colourless crystals in92% yield. ¹H-NMR (CDCl₃) δ 7.54 (d, 1H), 7.20-7.13 (m, 5H), 6.83 (d,1H), 5.88 (s, 1H), 4.24 (dd, 2H), 4.17 (dd, 2H), 3.96 (t, 2H), 3.80 (t,2H), 2.18-2.12 (m, 4H), 1.35 (d, 1H).

2-[4-(4-Bromo-butoxy)-2′-methyl-biphenyl-3-yl]-[1,3]dioxane

General procedure L gave the title compound as colourless crystals in61% yield. ¹H-NMR (CDCl₃) 65 7.61 (d, 1H), 7.28-7.21 (m, 5H), 6.91 (d,1H1), 5.92 (s, 1H), 4.27 (dd, 2H), 4.12-4.00 (m, 4H), 3.58 (t; 2H),2.28-2.01 (m, 8H), 1.45 (d, 1H).

2-[4-(5-Bromo-pentyloxy)-2′-methyl-biphenyl-3-yl]-[1,3]dioxane

General procedure L gave the title compound as colourless oil in 48%yield. ¹-NMR (CDCl₃) δ 7.61 (d, 1H), 7.28-7.20 (m, 5H), 6.91 (d, 1H),5.93 (s, 1H), 4.27 (dd, 2H), 4.09-4.00 (m, 4H), 3.50 (t, 2H), 2.27-2.22(m, 4H), 2.06-1.69 (m, 6H), 1.44 (d, 1H).

4-[2-(tert-Butyl-methyl-amino)-ethoxy]-2′-methyl-biphenyl-3-carbaldehyde

General procedure K gave the title compound as colourless crystals in68% yield. ¹H-NMR (CDCl₃) δ 10.49 (s, 1H), 7.72 (d, 1H), 7.42 (dd, 1H),7.18-7.13 (m, 4H), 6.97 (d, 1H), 4.09 (t, 2H), 2.81 (t, 2H), 2.29 (s,3H), 2.18 (s, 3H), 1.05 (s, 9H).

2′-Methyl-4-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-3-carbaldehyde

General procedure K gave the title compound as yellow crystals in 75%yield. ¹H-NMR (CDCl₃) δ 10.35 (s, 1H), 7.61 (d, 1H), 7.32 (dd, 1H),7.08-6.99 (m, 4H), 6.87 (d, 1H), 4.22 (bs, 2H), 2.76 (bs, 2H), 2.23 (bs,2H), 2.06 (s, 3H), 0.98 (bs, 2H).

4-(2-Diethylamino-ethoxy)-2′-methyl-biphenyl-3-carbaldehyde

General procedure K gave the title compound as an yellow in 75°/% yield.¹H-NMR (CDCl₃) δ 10.35 (s, 1H), 7.63 (d, 1H), 7.33 (dd, 1H), 7.09-7.01(m, 4H), 6.88 (d, 1H), 4.10 (t, 2H), 2.86 (t, 2H), 2.56 (bs, 4H), 2.08(s, 3H), 0.97 (t, 6H).

4-[4-(tert-Butyl-methyl-amino)-butoxy]-2′-methyl-biphenyl-3-carbaldehyde

General procedure K gave the title compound as an yellow oil in 37%yield. ¹H-NMR (CDCl₃) δ 10.49 (s, 1H), 7.73 (d, 1H), 7.43 (dd, 1H),7.19-7.12 (m, 4H), 6.97 (d, 1H), 4.09 (t, 2H), 2.37 (t, 2H), 2.19 (s,3H), 2.15 (s, 3H), 1.88-1.79 (m, 2H), 1.64-1.54 (m, 2H), 1.00 (s, 9H).

4-(4-Diethylamino-butoxy)-2′-methyl-biphenyl-3-carbaldehyde

General procedure K gave the title compound as an yellow oil in 35%yield. ¹H-NMR (CDCl₃) δ 10.60 (s, 1H), 7.84 (d, 1H), 7.54 (dd, 1H),7.30-7.22 (m, 4H), 8.07 (d, 1H), 4.20 (t, 2h), 2.62-2.53 (m, 6H), 2.30(s, 3H), 1.96-1.89 (m, 2H), 1.75-1.69 (m, 2H), 1.07 (t, 6H).

2′-Methyl-4-(4-pyrrolidin-1-yl-butoxy)-biphenyl-3-carbaldehyde

General procedure K gave the title compound as an yellow oil in 52%yield. ¹H-NMR (CDCl₃) δ 10.35 (s, 1H), 7.60 (d, 1H), 7.29 (dd, 1H),7.06-6.98 (m, 4H), 6.83 (d, 1H), 3.96 (t, 2H), 2.36-2.29 (m, 6H), 2.06(s, 3H), 1.76-1.71 (m, 2H), 1.61-1.52 (m, 6H).

2′-Methyl-4-(4-methylamino-butoxy)-biphenyl-3-carbaldehyde

General procedure K gave the title compound as an yellow oil in 19%yield. ¹H-NMR (CDCl₃) δ 10.47 (s, 1H), 7.73 (d, 1H), 7.43 (dd, 1H),7.19-7.13 (m, 4H), 6.68 (d, 1H), 4.09 (t, 2H), 2.63 (t, 2H), 2.40 (s,3H), 2.19 (s, 3H), 1.90-1.83 (m, 2H), 1.69-1.63 (m, 2H).

4-[5-(tert-Butyl-methyl-amino)-pentyloxy]-2′-methyl-biphenyl-3-carbaldehyde

General procedure K gave the title compound as an yellow oil in 37%yield. ¹H-NMR (CDCl₃) δ 10.49 (s, 1H), 7.73 (d, 1H), 7.43 (dd, 1H),7.19-7.13 (m, 4H), 6.96 (d, 1H), 4.07 (t, 2H), 2.32-2.31 (m, 2H), 2.19(s, 3H), 2.15 (s, 3H), 1.84-1.81 (m, 4H), 1.50-1.45 (m, 4H), 0.99 (s,9H).

4-(3-Dimethylamino-propoxy)-2′-methyl-biphenyl-3-carbaldehyde

General procedure F gave the title compound as an yellow oil in 57%yield. ¹H-NMR (CDCl₃) δ 10.57 (s, 1H), 7.82 (d, 1H), 7.52 (dd, 1H),7.28-7.21 (m, 4H), 7.08 (d, 1H), 4.23 (t, 2H), 2.55 (t, 2H), 2.38-2.24(m, 5H).

5-Bromo-2-(2-dimethylamino-ethoxy)-benzaldehyde

General procedure E gave the title compound as a yellow oil in 65%yield. ¹H-NMR (CDCl₃) δ 10.43 (s, 1H), 7.94 (d, 1H), 7.63 (dd, 1H), 6.92(d, 1H), 4.19 (t, 2H), 2.81 (t, 2H), 2.37 (s, 6H).

4-(2-Dimethylamino-ethoxy)-biphenyl-3-carbaldehyde

General procedure G gave the title compound as yellow, crystals in ⁵⁷%yield. ¹H-NMR (CDCl₃) δ 10.48 (s, 1H), 8.01 (d, 1H), 7.71 (dd, 1H), 7.49(d, 1H), 7.36 (t, 2H), 7.26 (t, 1H), 7.00 (d, 1H), 4.18 (t, 2H), 2.77(t, 2H), 2.31 (s, 6H).

4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-carbaldehyde

General procedure G gave the title compound as white crystals in 79%yield. ¹H-NMR (CDCl₃) δ 10.56 (s, 1H), 7.82 (d, 1H), 7.51 (dd, 1H),7.28-7.16 (m, 4H), 7.05 (d, 1H), 4.25 (t, 2H), 2.84 (t, 2H), 2.38 (s,6H), 2.26 (s, 3H).

4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-carbaldehyde

General procedure G gave the title compound as light yellow crystals in78% yield. ¹H-NMR (DMSO-d₆) δ 10.40 (s, 1H), 7.80-7.72 (m, 2H),7.38-7.25 (m, 3H), 7.11 (d, 1H), 7.03 (t, 1H), 4.25 (t, 2H), 3.76 (s,3H), 2.72 (t, 2H), 2.25 (s, 6H).

4-(2-Dimethylamino-ethoxy)-[1,1′;4′,1″]terphenyl-3-carbaldehyde

General procedure G gave the title compound as light yellow crystals in31% yield. ¹H-NMR (CDCl₃) δ 10.49 (s, 1H), 8.06 (d, 1H), 7.76 (dd, 1H),7.59-7.55 (m, 6H), 7.39 (dd, 2H), 7.31 (dd, 1H), 7.02 (d, 1H), 4.18 (t,2H), 2.77 (t, 2H), 2.31 (s, 6H).

4-(2-Dimethylaminoethoxy)-2′-trifluoromethoxy-biphenyl-3-carbaldehyde

General procedure G gave the title product as yellow oil in 40% yield.¹H-NMR (DMSO-d₆) δ 10.41 (s, 3H), 7.78-7.74 (m, 2H), 7.58-7.45 (m, 4H),7.40-7.36 (m, 1H), 4.28 (t, 2H), 2.72 (t, 2H), 2.24 (s, 6H).

2′-tert-Butoxymethyl-4-(2-dimethylamino-ethoxy)-biphenyl-3-carbaldehyde

General procedure G gave the title product as yellow oil in 65% yield.¹H-NMR (DMSO-d₆) δ 10.44 (s, 1H), 7.83 (d, 1H), 7,70 (dd, 1H), 7.46-7.41(m, 1H), 7.39-7.32 (m, 3H), 7.29-7.23 (m, 1H), 4.27 (t, 2H), 4.18 (s,2H), 2.72 (t, 2H), 2.25 (s, 6H), 1.13 (s, 9H).

4-(2-Dimethylamino-ethoxy)-2′,5′-dimethoxy-biphenyl-3-carbaldehyde

General procedure G gave the title product as yellow oil in 72% yield.¹H-NMR (DMSO-d₆) δ 10.40 (s, 1H), 7.79-7.75 (m, 2H), 7.29 (d, 1H), 7.04(d, 1H), 6.89 (dd, 1H), 6.86 (d, 1H), 4.26 (t, 2H), 3.74 (s, 3H), 3.70(s, 3H), 2.72 (t, 2H), 2.24 (s, 6H).

4-(2-Dimethylamino-ethoxy)-2′,4′-dimethoxy-biphenyl-3carbaldehyde

General procedure G gave the title product as orange oil in 53%, yield.¹H-NMR (DMSO-d₆) δ 10.40 (s, 1H), 7.73 (s, 3H), 7.71 (dd, 1H), 7.27 (dd,1H), 7.21 (d, 1H), 6.66 (d, 1H), 6.60 (dd, 1H), 4.25 (t, 2H), 3.80 (s,3H), 3.76 (s, 3H), 2.71 (t, 2H), 2.24 (s, 6H).

4-(2-Dimethylamino-ethoxy)-2′,4′,6′-trimethyl-biphenyl-3-carbaldehyde

General procedure G gave the title product as brown crystals in 45%yield. ¹H-NMR (DMSO-d₆) δ 10.41 (s, 1H), 7.40 (dd, 1H), 7.37 (d, 1H),7.32 (d, 1H), 6.93 (s, 2H), 4.26 (t, 2H), 2.73 (t, 2H), 2.25 (s, 9H),1.92 (s, 6H).

4-(2-Dimethylamino-ethoxy)-2′-methoxymethyl-biphenyl-3-carbaldehyde

General procedure G gave the title product as yellow oil in 51% yield.¹H-NMR (DMSO-d₆) δ 10.43 (s, 1H), 7.69 (s, 1H), 7.68 (dd, 1H), 7.51-7.46(m, 1H), 7.41-7.26 (m, 4H), 4.27 (t, 2H), 4.23 (s, 2H), 3.23 (s, 3H),2.73 (t, 2H), 2.24 (s, 6H).

4-(2-Dimethylamino-ethoxy)-2′,6′-dimethoxy-biphenyl-3-carbaldehyde

General procedure G gave the title product as yellow oil in 13% yield.¹H-NMR (DMSO-d₆) δ 10.39 (s, 1H), 7.66-7.46 (m, 4H), 7.33-7.22 (m, 1H),6.74 (d, 1H), 4.24 (t, 2H), 3.66 (s, 6H), 2.72 (t, 21H), 2.25 (s, 6H).

2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-carbaldehyde

General procedure G gave the title product as yellow oil in 45% yield.¹H-NMR (DMSO-d₆) δ 10.41 (s, 1H), 7.72 (s, 1H), 7.71 (dd, 1H), 7.56-7.52(m, 1H), 7.42-7.32 (m, 4H), 4.26 (t, 2H), 2.72 (t, 2H), 2.23 (s, 6H).

2′-Bromo-4-(2-dimethylamino-ethoxy)-biphenyl-3-carbaldehyde

General procedure G, using4-(2-dimethylamino-ethoxy)-3-formyl-benzeneboronic acid and1-bromo-2-iodo-benzene gave the title product as yellow oil in 68%yield. ¹H-NMR (CDCl₃) δ 10.51 (s, 1H), 7.90 (d, 1H), 7.70-7.65 (m, 2H),7.41-7.20 (m, 3H), 7.09 (d, 1H), 4.40 (t, 2H), 3.04 (bs, 2H), 2.56 (s,6H).

4-(2-Dimethylamino-ethoxy)-2′-methylsulfanyl-biphenyl-3-carbaldehyde

General procedure G gave the title product as yellow oil in 31% yield.¹H-NMR (DMSO-d₆) δ 10.41 (s, 1H), 7.66 (s, 1H), 7.65 (dd, 1H), 7.42-7.31(m, 3H), 7.23-7.19 (m, 2H), 4.27 (t, 2H), 2.73 (t, 2H), 2.37 (s, 3H),2.25 (s, 6H).

4-(2-Dimethylamino-ethoxy)-2′-trifluoromethyl-biphenyl-3-carbaldehyde

General procedure G gave the title product as yellow oil in 69% yield.¹H-NMR (DMSO-d₆) δ 10.41 (s, 1H), 7.82 (d, 1H), 7.72 (t, 1H), 7.65-7.56(m, 3H), 7.41 (d, 1H), 7.34 (d, 1H), 4.27 (t, 2H), 2.73 (t, 2H), 2.24(s, 6H).

4-(2-Dimethylamino-ethoxy)-2′-hydroxy-biphenyl-3-carbaldehyde

General procedure G gave the title product as brown oil in quantitativeyield. ¹H-NMR (DMSO-d₆) δ 10.42 (s, 1H), 9.63 (br, 1H), 7.89 (d, 1H),7.83 (dd, 1H), 7.29 (d, 1H), 7.26 (dd, 1H), 7.16 (td, 1H), 6.94 (dd,1H), 6.87 (td, 1H), 4.26 (t, 2H), 2.73 (t, 2H), 2.25 (s, 6H).

4-(2-Dimethylamino-ethoxy)-2′-ethyl-biphenyl-3-carbaldehyde

General procedure G gave the title product as brown oil in quantitativeyield. ¹H-NMR (DMSO-d₆) 10.42 (s, 1H), 7.61 (dd, 1H), 7.56 (d, 1H),7.35-7.31 (m, 3H), 7.27-7.21 (m, 1H), 7.15 (d, 1H), 4.28 (t, 2H), 2.75(t, 2H), 2.53 (q, 2H), 2.27 (s, 6H), 1.03 (t, 3H).

[2-(2′,6′-Dichloro-biphenyl-4-yloxy)-ethyl]-dimethyl-amine

General procedure M gave the title product as brown oil in 90% yield.¹H-NMR (DMSO-d₆) δ 7.57 (d, 1H), 7.54 (s, 1H), 7.42-7.37 (m, 1H), 7.17(d, 2H), 7.03 (d, 2H), 4.10 (t, 2H), 2.65 (t, 2H).

2′,6′-Dichloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-carbaldehyde

General procedure J gave the title product as brown crystals in 88%yield. 1H-NMR (CDCl₃), δ 10.61 (s, 1H), 7.83 (d, 1H), 7.52 (dd, 1H),7.47 (d, 1H), 7.44 (s, 1H), 7.33-7.28 (m, 1H), 7.15 (d, 1H), 4.33 (t,2H), 2.91 (t, 2H), 2.45 (s, 6H).

2′,6′-Difluoro-biphenyl-4-ol

General procedure G using 4-Hydroxyphenylboronic acidO-tetrahydropyranyl ether and 2-Bromo-1,3-difluoro-benzene, followed bysubsequent deprotection gave the title product as beige crystals inquantitative yield. ¹H-NMR (DMSO-d₆) δ 9.72 (s, 1H), 7.45-7.35 (m, 1H),7.27-7.22 (m, 2H), 7.20-7.13 (m, 2H), 6.87 (dt, 2H).

[2-(2′,6′-Difluoro-biphenyl-4-yloxy)-ethyl]-dimethyl-amine

General procedure M gave the title product as dark brown crystals inquantitative yield. ¹H-NMR (DMSO-d₆) δ 7.48-7.40 (m, 1H), 7.39-7.33 (m,2H), 7.22-7.15 (m, 2H), 7.05 (dt, 2H), 4.10 (t, 2H), 2.64 (t, 2H), 2.22(s, 6H).

4-(2-Dimethylamino-ethoxy)-2′,6′-difluoro-biphenyl-3-carbaldehyde

General procedure J gave the title product as brown oil in 57% yield.¹H-NMR (DMSO-d₆) δ 10.41 (s, 1H), 7.77-7.72 (m, 2H), 7.66-7.37 (m, 2H),7.23 (t, 2H), 4.29 (t, 2H), 2.73 (t, 2H), 2.25 (s, 6H).

4-(4-Dimethylamino-butoxy)-2′-methyl-biphenyl-3-carbaldehyde

General procedure K gave the title product as orange oil in 19% yield.¹H-NMR (DMSO-d₆) δ 10.43 (s, 1H), 7.64 (dd, 1H), 7.59 (d, 1H), 7.32-7.17(m, 5H), 4.21 (t, 2H), 2.27 (t, 2H), 2.22 (s, 3H), 2.13 (s, 6H), 1.82(p, 2H), 1.60 (p, 2H).

4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-carbaldehyde

General procedure G gave the title compound as colourless crystals in81% yield. ¹H-NMR (DMSO-d₆) δ 10.41 (s, 1H), 7.94-7.89 (m, 2H), 7.33 (d,1H), 7.24 (bs, 2H), 6.98 (bs, 1H), 4.25 (t, 2H), 2.71 (t, 2H), 2.32 (s,6H), 2.24 (s, 6H).

5-tert-Butyl-2-(2-dimethylamino-ethoxy)-benzaldehyde

General procedure E gave the title product as yellow oil in 93% yield.¹H-NMR (CDCl₃) δ 10.50 (s, 1H), 7.85 (d, 1H), 7.57 (dd, 1H), 6.93 (d,1H), 4.18 (t, 2H), 2.79 (t, 2H), 2.36 (s, 6H), 1.31 (s, 9H).

2-(2-Dimethylamino-ethoxy)-5-methyl-benzaldehyde

General procedure E gave the title product as yellow oil in 95% yield.¹H-NMR (CDCl₃) δ 10.48 (s, 1H), 7.63 (d, 1H), 7.34 (dd, 1H), 6.89 (d,1H), 4.16 (t, 2H), 2.79 (t, 2H), 2.35 (s, 6H), 2.31 (s, 3H).

3,5-Di-tert-butyl-2-(2-dimethylamino-ethoxy)-benzaldehyde

General procedure E gave the title product as yellow oil in 35% yield.¹H-NMR (CDCl₃) δ 10.39 (s, 1H), 7.72 (d, 1H), 7.63 (d, 1H), 4.05 (t,2H), 2.83 (t, 2H), 1.45 (s, 6H), 1.33 (s, 9h), 1.29 (s, 9H).

5-tert-Butyl-2-(3-dimethylaminopropoxy)-benzaldehyde

General procedure F gave the title product as yellow oil in 56% yield.¹H-NMR (CDCl₃) δ 10.52 (s, 1H), 7.86 (d, 1H), 7.58 (dd, 1H), 6.96 (d,1H), 4.15 (t, 2H), 2.49 (t, 2H), 2.27 (s, 6H), 2.02 (hep, 2H), 1.33 (s,9H).

2-(2-Dimethylamino-ethoxy)-5-propyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde

General procedure E gave the title compound as brown crystals in 15%yield. ¹H-NMR (CDCl₃) δ 10.36 (s, 1H), 7.65 (s, 1H), 6.78 (s, 1H), 5.56(s, 1H), 4.24-4.12 (m, 2H), 3.88-3.64 (m, 2H), 2.81 (t, 2H), 2.61-2.55(m, 2H), 2,38 (s, 6H), 2.05-1.57 (m, 8H), 0.96 (t, 3H).

2-Hydroxy-5-(tetrahydro-pyran-2-yloxy)-benzaldehyde

A solution of 2,5-dihydroxy-benzaldehyde (152 mmol),3,4-dihydro-2H-pyran (167 mmol) and a catalytic amount of pyridiniump-toluenesulfonate in CH₂Cl₂ (480 mL) was left overnight at roomtemperature. The organic phase was washed with 1 N Na7CO₃ (aq) (3×100mL) and dried (Na₂SO₄). Evaporation in vacuo gave the desired product asbrown crystals that was used without further purification. ¹H-NMR(CDCl₃) δ 10.72 (s, 1H), 9.88 (s, 1H), 7.32-7.29 (m, 2H), 6.96 (d, 1H),5.38 (bs, 1H), 3.99-3.91 (m, 1H), 3.69-3.64 (m, 1H), 2.06-1.63 (m, 6H).

2-(2-Dimethylamino-ethoxy)-5-(tetrahydro-pyran-2-yloxy)-benzaldehyde

General procedure E gave the title compound as an yellow oil in 86%yield. ¹H-NMR (CDCl₃) δ 10.46 (s, 1H), 7.50 (d, 1H), 7.27-7.23 (m, 1H),6.93 (d, 1H), 5.35 (t, 1H), 4.15 (t, 2H), 3.94-3.86 (m, 1H), 3.63-3.57(m, 2H), 2.77 (t, 2H), 2.35 (s, 6H), 2.01-1.55 (m, 6H).

5-(1,1-Dimethyl-allyl)-2-hydroxy-benzaldehyde

A solution of boron trichloride (1M in CH₂Cl₂, 39.7 mmol) was addeddropwise under argon at −78° C. to a stirred solution of5-(1,1-Dimethyl-allyl)-2-methoxy-benzaldehyde (13.2 mmol) in dry CH₂Cl₂(120 ml). The dry ice—acetone bath was removed and reaction allowedwarming to RT. Stirred at RT for 18 hours, before the reaction mixturewas cooled to 0° C. and iced water (125 ml) slowly added. Extracted withCH₂Cl₂ (2×100 ml). The organic phases were washed with brine, dried(Na₂SO₄), filtered, and evaporated to black oil. Purified by flashchromatography (heptane:EtOAc) to give the title product as yellow oilin 56% yield. ¹H-NMR (CDCl₃) δ 10.82 (s, 1H), 9.81 (s, 1H), 7.43 (d,1H), 7.41 (s, 1H), 6.86 (d, 1H), 5.92 (dd, 1H), 5.02-4.96 (m, 2H), 1.34(s, 6H).

5-(1,I-Dimethyl-allyl)-2-(2dimethylamino-ethoxy)-benzaldehyde

General procedure E gave the title product as yellow oil in 41%) yield.¹H-NMR (CDCl₃) δ 10.42 (s, 1H), 7.75 (d, 1H), 7.44 (dd, 1H), 6.85 (d,1H), 5.96-5.86 (m, 1H),4.99-4.93 (m, 2H), 4.11 (t, 2H), 2.72 (t, 2H),2.28 (s, 6H), 1.32 (s, 6H).

2′-Methyl-4-(5-pyrrolidin-1-yl-pentyloxy)-biphenyl-3-carbaldehyde,

General procedure K gave the title product as brown oil in 34% yield.¹H-NMR (CDCl₃) δ 10.48 (s, 1H), 7.73 (d, 1H), 7.43 (dd, 1H), 7.19-7.12(m, 4H), 6.95 (d, 1H), 4.07 (t, 2H), 2.54-2.46 (m, 6H), 2.17 (s, 3H),1.90-1.74 (m; 6H), 1.64-1.47 (m, 4H).

4-(2-Dimethylamino-ethoxy)-3-formyl-benzeneboronic acid

A stirred solution of[²-(⁴-bromo-2-[1,3]dioxan-2-yl-phenoxy)-ethyl]-dimethyl-amine (15 mmol)in dry THF (100 mL) was cooled to −78° C. and added n-BuLi (16.5 mmol)dropwise. The reaction was left for 30 min at −78° C. and addedtriisopropyl borate (22.5 mmol). The reaction was heated to roomtemperature, was added 2M HCl (aq, 50 mL) and was left for anadditional, hour. The mixture was added 1M Na₂CO₃ to neutral pH and wasextracted with EtOAc. The organic phase was washed with water, dried(Na₂SO₄) and evaporated in vacuo. Addition of EtOAc afforded beigecrystals that was filtered of and was used without further purification.

2-(2-Dimethylamino-ethoxy)-5-pyridin-3-yl-benzaldehyde

General procedure G using4-(2-dimethylamino-ethoxy)-3-formyl-benzeneboronic acid and3-bromo-pyridine gave the title product as yellow oil in 13% yield.¹H-NMR (CDCl₃) δ 10.46 (s, 1H), 8.76 (d, 1H), 8.52 (dd, 1H), 8.00 (d,1H), 7.80 (dt, 1H), 7.72 (dd, 1H), 7.30 (ddd, 1H), 7.07 (d, 1H), 4.28(t, 2H), 2.90 (t, 2H), 2.42 (s, 6H).

2-(2-Dimethylamino-ethoxy)-5-pyridin-2-yl-benzaldehyde

General procedure G using4-(2-dimethylamino-ethoxy)-3-formyl-benzeneboronic acid and2-bromo-pyridine gave the title product as yellow oil in 40% yield.¹H-NMR (CDCl₃) δ 10.47 (s, 1H), 8.60(dt, 1H), 8.34 (d, 1H), 8.26 (dd,1H), 7.69-7.67 (m, 2H), 7.17-7.14 (m, 1H), 7.05 (d, 1H), 4.24 (t, 2H),2.83 (t, 2H), 2.36 (s, 6H).

4-(2-Dimethylamino-ethoxy)-3′-methyl-biphenyl-3-carbaldehyde

General procedure G gave the title product as orange oil in 66% yield.¹H-NMR (CDCl₃) δ 10.27 (s, 1H), 7.80 (dd, 1H), 7.76 (d, 1H), 7.32-7.17(m, 4H), 7.02 (d, 1H), 4.13 (t, 2H), 2.57 (t, 2H), 2.23 (s, 3H), 2.10(s, 6H).

4-(2-Dimethylamino-ethoxy)-4′-methyl-biphenyl-3-carbaldehyde

General procedure G gave the title product as yellow oil in 58% yield.¹H-NMR (CDCl₃) δ 10.53 (s, 1H), 8.06 (d, 1H), 7.77 (dd, 1H), 7.47 (d,2H), 7.24 (d, 2H), 7.06 (d, 1H), 4.28 (t, 2H), 2.88 (t, 2H), 2.42 (s,6H), 2.38 (s, 3H).

3-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-4-carbaldehyde

A solution of 2,4-dihydroxybenzaldehyde (27 mmol) in methylene chloride(10 ml) and pyridine (30 mmol) was slowly added trifluoromethanesulfonicanhydride (32 mmol) keeping the temperature below 5° C. After 10 min themixture was washed with water and the organic phase was concentratedunder reduced pressure. The crude brown oil (5 g), ortho-tolylboronicacid (20.4 mmol), sodium carbonate (55.5 mmol) anddichlorobis(triphenylphosphine)-palladium (II) (3 mol %) was dissolvedin DME (50 ml) and water (20 ml). The mixture was refluxed for 17 hunder Argon, cooled to room temperature and extracted with ethylacetate. The crude black oil (4.6 g) was dissolved in DMF (75 ml) andsodium hydride (60% in oil, 22.5 mmol) was slowly added. A solution of2-dimethylamino ethylchloride (22.5 mmol) in toluene (120 ml) was addedand the mixture was heated at 80° C. for 3 days. The mixture was washedwith saturated sodium bicarbonate, concentrated under reduced pressureand purified by chromatography. The resulting yellow oil was washed withhot heptane giving the product as relative pure oil (GC-MS). ¹H-NMR(DMSO-d₆) δ 10.41 (s, 1H), 7.74 (d, 2H), 7.66-7.55 (m, 1H), 7.36-6.79(m, 4H), 4.27 (t, 2H), 2.70 (t, 2H), 2.27 (s, 3H), 2.23 (s, 6H).

5-(2-Dimethylamino-ethoxy)-biphenyl-3-carbaldehyde

A solution of 3,5-dihydroxybenzaldehyde (14.4 mmol) and pyridine (114mmol) in methylene chloride (20 ml) was slowly addedtrifluoromethanesulfonic anhydride (36.2 mmol) keeping the temperaturebelow 5° C. After 10 min the mixture was washed with water and theorganic phase was concentrated under reduced pressure. The crude browncrystals (6.4 g—product and pyridine −1:1), phenylboronic acid (13.2mmol), sodium carbonate (39.6 mmol) anddichlorobis(triphenylphosphine)-palladium (II). (3 mol %) was dissolvedin DME (40 ml) and water (20 ml). The mixture was refluxed for 17 hunder Argon, cooled to room temperature and extracted with ethylacetate. Purification by chromatography yielded5-Hydroxy-biphenyl-3-carbaldehyde

as white crystals (7 mmol). ¹H-NMR (DMSO): δ 10.11 (s, 1H), 10.00 (s,1H), 7.69-7.66 (m, 3H), 7.51-7.46 (bt, 2H), 7.41 (m, 1H), 7.36 (t, 1H),7.26 (t, 1H).

The product (7 mmol) and 2-dimethylamino ethylchloride,hydrochloride(14.1 mmol) was dissolved in DMF (40 ml), and sodium hydride (60% inoil, 22.6 mmol) was slowly added. The mixture was heated at 100° C. for18 hours, partitioned between methylene chloride and saturated sodiumbicarbonate, and concentrated under reduced pressure. Flashchromatography gave a crude yellow oil consisting of5-(2-Dimethylamino-ethoxy)-biphenyl-3-carbaldehyde (˜1.7 mmol) and DMF(1:10 mixture). 1H-NMR (DMSO-d₆): δ 10.05 (s, 1H), 7.81-7.75 (m, 3H),7.55-7.42 (m, 5H), 4.22 (t, 2H), 2.67 (t, 2H), 2.24 (s, 6H).

Chalcone Synthesis

C001:(E)-3-[2-(2-Dimethylamino-ethoxy)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure I gave the title product as yellow oil in 7% yield.¹H-NMR (CDCl₃) δ 8.04 (d, 1H), 7,66 (dd, 1H), 7.54 (d, 1H), 7.47 (d,1H), 7.38 (dd, 1H), 7.00 (t, 1H), 6.94 (d, 1H), 6.77 (d, 1H), 4.16 (t,2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.92 (s, 3H), 2.83 (t, 2H), 2.35 (s,6H).

C002:(E)-3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-(2-fluoro4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as colourlesscrystals in 19% yield. ¹H-NMR (DMSO-d₆) δ 7.63 (dd, 1H), 7,57 (dd, 1H),7.36-7.30 (m, 2H), 7.00 (dd, 1H), 6.81-6.67 (m, 3H), 6.36 (s, 2H), 3.92(t, 2H), 3.63 (s, 3H), 2.56 (t 2H), 2.06 (s, 6H), 2.04 (s, 3H).

C003:(E)-3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-(2,3,4trimethoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 16% yield. ¹H-NMR (DMSO-d₆) δ 7.89 (d, 1H), 7,67 (d, 1H),7.55 (d, 1H), 7.43 (d, 1H), 7.33 (dd, 1H), 7.13 (d, 1H), 7.05 (d, 1H),6.71 (s, 2H), 4.28 (t, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.91 (s, 3H),2.93 (t, 2H), 2.40 (s, 6H), 2.39 (s, 3H).

C004:(E)-3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 39% yield. ¹H-NMR (DMSO-d₆) δ 7.69 (dd, 1H), 7.61 (dd, 1H),7.52 (dd, 1H), 7.44 (dd, 1H), 7.25 (dd, 1H), 6.86 (d, 1H), 6.81-6.72 (m,2H), 6.40 (s, 2H), 3.99 (t, 2), 3.68 (s, 3H), 2.63 (t, 2H), 2.12 (s,6H), 1.10 (s, 9H).

C005:(E)-3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 20% yield. ¹H-NMR (DMSO-d₆) δ 7.75 (d, 1H), 7.67 (d, 1H),7.48 (d, 1H), 7.40 (dd, 1H), 7.29 (d, 1H), 7.01 (d, 1H), 6.90 (d, 1H),6.57 (s, 2H), 4.12 (t, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H),2.73 (t, 2H), 2.22 (s, 6H), 1.27 (s, 9H).

C006:(E)-3-[2-(2-Dimethylamino-ethoxy)-5-hydroxy-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure H gave the title product as yellow crystals in 16%yield. ¹H-NMR (CDCl₃) δ 9.18 (bs, 1H), 7.76 (d, 1H), 7.36 (d, 1H), 7.32(d, 1H), 7.09 (d, 1H), 6.96-6.92 (m, 2H), 6.82 (dd, 1H), 4.02 (t, H),3.87 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.61 (t, 2H), 2.17 (s, 6H).

C007:(E)-3-[2-(2-Dimethylamino-ethoxy)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 45% yield. ¹H-NMR (DMSO-d₆) δ 7.90 (dd, 1H), 7.82-7.76 (m,2H), 7.59 (dd, 1H), 7.43 (dd, 1H), 7.14 (d, 1H), 7.05-6.91 (m, 3H), 6.56(s, 1H), 4.21 (t, 2H), 3.87 (s, 3H), 2.85 (t, 2H), 2.33 (s, 6H).

C008:(E)-3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 25% yield. ¹H-NMR (DMSO-d₆) δ 7.67-7.46 (m, 6H), 7.30 (d,1H), 7.23 (dd, 1H), 7.00 (d, 1H), 6.58 (s, 4H), 4.20 (t, 2H), 3.70 (s,2H), 2.95 (t, 2H), 2.38 (s, 6H), 2.27 (s, 3H), 2.23 (s, 6H).

C009:N-(2-{3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-(E)-acryloyl}-phenyl)-benzenesulfonamide

General procedure H gave the title product as yellow crystals in 48%yield. ¹H-NMR (CDCl₃) δ 8.02-7.97 (m, 2H), 7.91-7.88 (m, 2H), 7.79 (dd,1H), 7.70 (d, 1H), 7.55-7.41 (m, 5H), 7.24 (dd, 1H), 7.18 (dt, 1H) 6.92(d, 1H), 4.21 (t, 2H), 2.87 (t, 2H), 2.41 (s, 6H), 2.39 (s, 3H).

C010:(E)-3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 73% yield. ¹H-NMR (DMSO-d₆) δ 8.22-8.16 (m, 3H), 8.05 (d,2H), 7.77-7.71 (m, 3H), 7.47 (t, 2H), 7.35 (t, 1H), 7.23 (d, 1H), 7.09(d, 2H), 6.58 (s, 2H), 4.31 (t, 2H), 3.87 (s, 3H), 2.99 (t, 2H), 2.45(s, 6H).

C011:(E)-3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 77% yield. ¹H-NMR (DMSO-d₆) δ 8.07 (d, 1H), 7.96 (d, 1H),7.84 (t, 1H), 7.77-7.70 (m, 4H), 7.48 (t, 2H), 7.34 (t, 1H), 7.23 (d,1H), 7.00-6.91 (m, 2H), 6.58 (s, 2H), 4.30 (t, 2H), 3.87 (s, 3H), 2.96(t, 2H), 2.41 (s, 6H).

C012:(E)-3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as colourlesscrystals in 84% yield. ¹H-NMR (DMSO-d₆) δ 8.03 (d, 1H), 7.85 (d, 1H),7.74-7.70 (m, 3H), 7.61 (d, 1H), 7.45 (t, 2H), 7.36-7.30 (m, 2H) 7.22(d, 1H), 6.94 (d, 1H), 6.58 (s, 2H), 4.27 (t, 2H), 3.87 (s, 3H), 3.82(s, 3H), 3.79 (s, 3H), 2.92 (t, 2H), 2.36 (s, 6H).

C013:(E)-1-(2-Chloro-4-methoxy-phenyl)-3-[4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title product as slightlyyellow crystals in 63% yield. ¹H-NMR (DMSO-d₆) δ 8.10 (d, 1H), 7.79 (d,1H), 7.75-7.71 (m, 2H), 7.62 (d, 1H), 7.54 (d, 1H), 7.45 (t, 2H), 7.34(t, 1H), 7.20 (d, 1H), 7.16 (d, 11t), 7.04 (dd, 1H), 6.57 (s, 2H), 4.26(t, 2H), 3.86 (s,3H), 2.91 (t, 2H), 2.35 (t, 6H).

C014:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-(4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as slightlyyellow crystals in 55% yield. ¹H-NMR (DMSO-d₆) 6 8.15 (d, 2H), 8.02 (d,2H), 7.95 (d, 1H), 7.53 (dd, 1H), 7.35 (t, 2H), 7.19-7.01 (m, 5H), 6.58(s, 1H), 4.26, (t, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 2.86 (t, 2H), 2.36(s, 6H).

C015:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 65% yield. ¹H-NMR (DMSO-d₆) δ 7.93 (d, 1H), 7.86-7.80 (m,2H), 7.63 (dd, 1H), 7.55 (dd, 1H), 7.37-7.32 (m, 2H), 7.18 (d, 1H), 7.12(d, 1H), 7.06-6.91 (m, 3H), 6.59 (s, 2H),4.27 (t, 2H), 3.87 (s, 3H),3.78 (s, 3H), 2.90 (t, 2H), 2.36 (s, 6H).

C016:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as slightlyyellow crystals in 60% yield. ¹H-NMR (DMSO-d₆) δ 7.85 (d, 1H), 7.83 (d,1H), 7.53 (dd, 1H), 7.50 (d, 1H), 7.37-7.31 (m, 3H), 7.17 (d, 1H), 7.11(d, 1H), 7.03 (t, 1H), 6.93 (d, 1H), 6.59 (s, 3H), 4.28 (t, 2H), 3.87(s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.78 (s, 3H), 2.96 (t, 2H), 2.40(s, 6H).

C017:(E)-1-(2-Chloro-4-methoxy-phenyl)-3-[4-(2-dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title product as slightlyyellow crystals in 37% yield. ¹H-NMR (DMSO-d₆) δ 7.84 (d, 1H), 7.76 (d,1H), 7.59 (d, 1H), 7.55 (dd, 1H), 7.40 (d, 1H), 7.36-7.31 (m, 2H),7.16-6.99 (m, 5H), 6.59 (s, 2H), 4.21 (t, 2H), 3.85 (s, 3H), 3.77 (s,3H), 2.78 (t, 2H), 2.26 (s, 6H).

C018:(E)-3-[2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as colourlesscrystals in 20% yield. ¹H-NMR (DMSO-d₆) δ 7.86-7.81 (m, 2H), 7.58-7.39(m, 6H), 7.35 (d, 1H), 7.22 (d, 1H), 6.93 (d, 1H), 6.59 (s, 2H), 4.26(t, H), 3.87 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 2.85 (t, 2H), 2.32 (s,6H).

C019:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as Yellowcrystals in 76% yield. ¹H-NMR (DMSO-d₆) δ 8.16 (d, 2H), 8.05 (s, 2H),7.94 (d, 1H), 7.38 (dd, 1H), 7.33-7.24 (m, 4H), 7.20 (d, 1H), 7.06 (d,2H) 6.58 (s, 2H), 4.30 (t, 2H), 3.86 (s, 3H), 2.96 (t, 2.43 (s, 6H),2.27 (s, 3H).

C020:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as slightlyyellow crystals in 73% yield. ¹H-NMR (DMSO-d₆) δ 7.94 (d, 1H), 7.83 (t,1H), 7.75 (d, 1H), 7.66 (dd, 1H), 7.40 (dd, 1H), 7.32-7.19 (m, 5H),6.98-6.89 (m, 2H), 6.58 (s, 2H), 4.29 (t, 2H), 3.86 (s, 3H), 2.94 (t,2H), 2.39 (s, 6H), 2.26 (s, 3H).

C021:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as slightlyyellow crystals in 73% yield. ¹H-NMR (DMSO-d₆) δ 7.84 (d, 1H), 7.70 (d,1H), 7.54 (d, 1H), 7.38 (dd, 1H), 7.34 (d, 1H), 7.30-7.22 (m, 4H), 7.19(d, 1H, 6.92 (d, 1H), 6.59 (s, 2H), 4.24 (t, 2H), 3.86 (s, 3H), 3.80 (s,3H), 3.78 (s, 3H), 2.83 (t, 2H), 2.30 (s, 6H), 2.26 (s, 3H).

C022:(E)-1-(2-Chloro-4-methoxy-phenyl)-3-[4-(2-dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 54% yield. ¹H-NMR (DMSO-d₆) δ 7.79 (d, 1H), 7.76 (d, 1H),7.60 (d, 1H), 7.45 (d, 1H), 7.40 (dd, 1H), 7.31-7.14 (m, 6H), 7.03 (dd,1H), 6.59 (s, 2H), 4.22 (t, 2H), 3.85 (s, 3H), 2.80 (t, 2H), 2.28 (s,6H), 2.25 (s,3H).

C023:(E)-3-[4-(2′-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as slightlyyellow crystals in 74% yield. ¹H-NMR (DMSO-d₆) δ 8.19-8.01 (m, 5H), 7.69(dd, 1H), 7.34 (bs, 2H), 7.21 (d, 1H), 7.10 (d, 2H), 6.98 (s, 1H), 6.59(s 2H), 4.29 (t, 2H), 3.87 (s, 3H), 2.94 (t, 2H), 2.42 (s, 6H), 2.35 (s,6H).

C024:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 73% yield. ¹H-NMR (DMSO,-d₆) δ 8.02 (d, 1H), 7.93 (d, 1H),7.83 (t, 1H), 7.73 (dd, 1H), 7.69 (t, 1H), 7.31 (bs, 2H), 7.20 (d, 1H),7.00-6.91 (m, 3H), 6.59 (s, 2H), 4.27 (t, 2H), 3.87 (s, 3H), 2.90 (t,2H), 2.36 (s, 6H), 2.33 (s, 6H).

C025:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 52% yield. ¹H-NMR (DMSO-d₆) δ 7.99 (d, 1H), 7.83 (d, 1H),7.68 (dd, 1H), 7.59 (d, 1H), 7.34 (d, 1H), 7.30 (bs, 2H), 7.19 (d, 1H),696 (bs, 1H), 6.93 (d, 1H), 6.58 (s, 2H), 4.27 (t, 2H), 3.87 (s, 3H),3.82 (s, 3H), 3.79 (s, 3H), 2.93 (t, 2H), 2.38 (s, 6H), 2.33 (s, 6H).

C026:(E)-1-(2-Chloro-4-methoxy-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 77% yield. ¹H-NMR (DMSO-d₆) δ 8.05 (d, 1H), 7.76 (d, 1H),7.71 (dd, 1H), 7.60 (d, 1H), 7.51 (d, 1H), 7.32 (bs, 2H), 7.18 (d, 1H)7.16 (d, 1H), 7.05 (dd, 1H), 6.96 (bs, 1H), 6.59 (s, 2H), 4.22 (t, 2H),3.86 (s, 3H), 2.82 (t, 2H), 2.33 (s, 6H), 2.29 (s, 6H).

C027:N-(2-{3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-(E)-acryloyl}-phenyl)-benzenesulfonamide

General procedure H gave the title product as yellow crystals in 33%yield. 1¹H-NMR (CDCl₃) δ 7.97 (dd, 1H), 7.93 (d, 1H), 7.87-7.84 (m, 2H),7.76 (dd, 1H), 7.73 (d, 1H), 7.54 (d, 1H), 7.51-7.37 (m, 5H), 7.14 (m,1H), 6.92 (d, 1H), 4.18 (t, 2H) 2.82 (t, 2H), 2.36 (s, 6H), 1.35 (s,9H).

C028:(E)-3-[3,5-Di-tert-butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the title product as yellow crystals in 11%yield. ¹H-NMR (CDCl₃) δ 7.97 (dd, 1H), 7,79 (dd, 1H), 7.42 (d, 1H), 7.35(d, 1H), 7.30 (dd, H), 6.72 (dd, 1H), 6.60 (dd, 1H), 3.85, (t, 2H), 3.81(s, 3H), 2.72 (t, 2H), 2.24 (s, 6H), 1.34 (s, 9H), 1.26 (s, 9H).

C029:(E)-3-[4-(2-Dimethylamino-ethoxy)-[1,1′;4′,1″]terphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the title product as yellow crystals in 23%yield. ¹H-NMR (CDCl₃) δ 8.06 (dd, 1H), 7.86-7.80 (m, 2H), 7.63-7.54 (m,41t), 7.39 (dd, 2H), 7.31 (s, 1H), 6.96 (d, 1H), 6.72 (dd, 1H), 6.59(dd, 1H), 4.15 (t, 2H), 3.81, (s, 3H), 2.80 (d, 2H), 2.30 (s, 2H).

C030:(E)-1-(2-Diethylaminomethyl-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title product as greencrystals in 33% yield. ¹H-NMR (DMSO-d₆) δ 8.02 (d, 1H), 7.67 (dd, 1H),7.61 (d, 1H), 7.47-7.38 (m 4H), 7.37 (d, 1H), 7.31 (br, 2H), 7.15 (d,1H) 6.96 (br, 1H), 6.59 (s, 3H) 4.19 (t, 2H), 3.86 (s, 2H), 2.78 (t,2H), 2.40 (q, 4H), 2.39 (s, 6H), 2.24 (s, 6H), 0.86 (t, 6H).

C031:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 40% yield. ¹H-NMR (DMSO-d₆) δ 7.85 (d, 1H), 7.59 (d, 1H),7.56-7.33 (m, 7H), 7.25 (d, 1H), 7.16-7.12 (dd, 2H), 7.04 (t, 1H), 6.61(s, H), 4.22 (t, 2H), 3.79 (s, 3H), 3.60 (s, 2H), 2.81 (s, 2H),2.50-2.30 (broad, 8H), 2.28 (s, 6H), 2.22 (s, 3,H).

C032:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure H gave the title product as yellow crystals in 39%yield. ¹H-NMR (CDCl₃) δ 7.63 (d, 1H), 7.55 (d, 1H), 7.41-7.24 (m, 9H),7.10 (d, 1H), 6.96 (d, 1H), 4.15 (t, 2H), 3.61 (s, 2H), 2.73 (t, 2H),2.40 (bs, 8H), 2.30 (s, 3H), 2.27 (s, 6H), 2.18 (s, 3H).

C033:(E)-3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-[2-(2-dimethylamino-ethoxy)-phenyl]-propenone

General procedure H gave the fumarate of the title product as colourlesscrystals in 15% yield. ¹H-NMR (DMSO-d₆) δ 7.79 (d, 1H), 7,59 (d, 1H),7.55-0.42 (m, 3H), 7.24-7.19 (m, 2H), 7.06 (dd, 1H), 7.00 (d, 1H), 6.58(s, 4H), 4.23 (t, 2H), 4.15 (t, 2H), 2.84 (t, 2H), 2.80 (t, 2H), 2.33(s, 6H), 2.27 (s, 3H), 2.26 (s, 6H).

C034:(E)-3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-[4-(2-dimethylamino-ethylamino)-phenyl]-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 14% yield. ¹H-NMR (DMSO-d₆) δ 8.16 (d, 1H), 8.08 (d, 1H),8.01 (d, 2H), 7.96 (d, 1H), 7.75 (d, 2H), 7.70 (dd, 1H), 7.47 (dd, 2H),7.35 (dd, 1H), 7.23 (d, 1H), 6.69 (d, 2H), 6.58 (s, 2H), 4.28 (t, 1H),3.32 (dt, 2H), 2.89 (t, 2H), 2.70 (t, 2H), 2.38 (s, 6H).

C035:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the fumarate of the title compound as palegreen crystals in 28% yield. ¹H-NMR (DMSO-d₆) δ 7.79 (d, 1H), 7.69 (d,1H), 7.55-7.37 (m, 5H), 7.28-7.22 (m, 5H), 7.16 (d, 1H), 6.59 (s, 4H),4.24 (t, 2H), 3.67 (s, 2H), 2.87 (t, 2H),2.32 (s, 6H), 2.26 (s, 3H),2.17 (s, 6H).

C036:(E)-3-[4-,(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H,gave the fumarate of the title compound as palegreen crystals in 29% yield. ¹H-NMR (DMSO-d₆) δ 7.86 (d, 1H), 7.68 (d,1H), 7.55-7.43 (m, 5H), 7.37-7.31 (m, 3H), 7.12 (t, 2H), 7.05 (t, 1H),6.58 (s, 4H), 4.25 (t, 2H), 3.76 (s, 3H) 3.68 (s, 2H), 2.91 (t, 2H),2.34 (s, 6H), 2.19 (s, 6H).

C037:(E)-3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(3-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as yellow oil in 42% yield.¹H-NMR (CDCl₃) δ 8.07 (d, 1H),7.90-7.88 (m, 2H), 7.77 (d, 1H), 7.71 (d,1H), 7.54-7.47 (m, 4H), 7.41-7.38 (m, 3H), 7.36-7.25 (m, 1H), 6.96 (d,1H), 4.15 (t, 2H), 3.44 (s, 2H),2.80 (t, 2H), 2.31 (s, 6H), 2.20 (s,6H).

C038:(E)-3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(2-diethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as a green oil in 42% yield.¹H-NMR (DMSO-d₆) δ 7.68 (d, 1H), 7.52 (d, 1H), 7.43-7.32 (m, 5H), 7.20(d, 1H), 6.98 (d, 1H), 4.04 (t, 2H), 3.59 (s, 2H), 2.54 (t (under DMSO),2H), 2.33 (q, 4H), 2.08 (s, 6H), 1.28 (s, 9H), 0.82 (t, 6H).

C039:(E)-3-[2-(2-Dimethylamino-ethoxy)-4-hydroxy-5-propyl-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 14%yield. ¹H-NMR (DMSO-d₆) δ 7,74-7,60 (m, 2H); 7,36-7,25 (m, 2H);6,86-6,78 (m; 2H); 6,48-6,41 (m, 2H); 3,97 (t, 2H); 3,75 (s, 3H); 2,66(t, 2H); 2,40-2,32 (m, 3H); 2,17 (s, 6H);1,46-1,39 (m, 2H); 0,81-0,76(t, 2H).

C040:(E)-3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(4-hydroxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 25%yield. ¹H-NMR (CDCl₃) δ 7.99 (d, 1H), 7.93 (d, 1H), 7.76 (d, 1H), 7.73(s, 1H), 7.52-7.47 (m, 3H), 7.36 (t, 2H), 7.28-7.23 (m, 1H), 6.95 (d,1H), 6.84 (dd, 2H), 4.14 (t, 2H), 2.79 (t, 2H), 2.31 (s, 6H).

C041:(E)-3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(4-hydroxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 47% yield. ¹H-NMR (DMSO-d₆) δ 8.05 (d, 2H), 7.95 (s, 2H),7.82 (d, 1H), 7.42 (d, 1H), 7.05 (d, 1H), 6.91 (d, 2H), 6.58 (s, 3H),4.24 (t, 2H), 3.00 (t, 2H), 2.46 (s, 6H), 1.32 (s, 9H).

C042:N-(2-{3-[5-tert-Butyl-2-(3-dimethylamino-propoxy)-phenyl]-(E)-acryloyl}-phenyl)-benzenesulfonamide

General procedure H gave the title compound as yellow crystals in 27%yield. ¹H-NMR (CDCl₃) δ 7.94 (d, 1H), 7.89-7.83 (m, 3H), 7.76 (dd, 1H),7.56 (d, 1H), 7.4 (d, 1H), 7.52-7.37 (m, 5H), 7.17-7.12 (m, 1H), 6.92(d, 1H), 4.14 (t, 2H) 2.50 (t, 2H), 2.26 (s, 6H), 2.06 (pen, 1H), 1.35(s, 9H).

C043:(E)-3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as slightlyyellow crystals in 9% yield. ¹H-NMR (CDCl₃) δ 7.39 (d, 1H), 7.33-7.27(m, 2H), 7.19-7.14 (m, 2H), 7.09 (bs, 1H), 7.00 (dd, 1H), 6.80 (d, 1H),6.59 (s, 2H), 4.29 (t, 2H), 382 (s, 3H), 3.76 (s, 3H), 3.73 (s, 3H),3.53 (t, 2H), 2.91 (s, 6H).

C044:(E)-3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as slightlyyellow crystals in 24% yield. ¹H-NMR (DMSO-d₆) δ 7.85 (t, 1H), 7.63 (d,1H), 7.52 (dd, 1H), 7.38-7.35 (m, 3H), 7.06-6.92 (m,3H), 6.57(s, 2H),4.20 (t, 2H), 3.87 (s, 3H), 2.51 (t, 2H), 2.41 (s, 6H).

C045:(E)-1-(2,4-Dimethoxy-phenyl)-3-[3-(2-dimethylamino-ethoxy)-phenyl]-propenone

General procedure H gave the fumarate of the title compound as slightlyyellow crystals in 24% yield. ¹H-NMR (DMSO-d₆) δ 7.61 (d, 1H), 7.55 (d,1H), 7.49 (d, 1H), 7.39-7.29 (m, 3H), 7.02 (dt, 1H), 6.69 (d, 1H), 6.65(dd, 1H), 6.57 (s, 2H), 4.20 (t, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.92(t, 2H), 2.42 (s, 6H).

C046:(E)-1-(2,5-Dimethoxy-phenyl)-3-[3-(2-dimethylamino-ethoxy)-phenyl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 33% yield. ¹H-NMR (DMSO-d₆) δ 7.32 (d, 1H), 7.24 (d, 1H),7.19-7.13 (m, 3H), 7.01-6.94 (m, 2H), 6.88-6.84 (m, 2H), 6.42 (s, 2H),4.01 (t, 2H), 3.65 (s, 3H), 3.59 (s, 3H), 2.67 (t, 2H), 2.20 (s, 6H).

C047:(E)-3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-(2-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound ascolourless crystals in 20% yield. ¹H-NMR (DMSO-d₆) δ 7.55 (dt, 1H), 7.49(dd, 1H), 7.44 (d, 2H), 7.38 (m, 3H), 7.20 (d, 1H), 7.09-7.00 (m, 2H),4.57 (s, 2H), 4.19 (t, 2H), 3.86 (s, 3H), 2.91 (t, 2H), 2.42 (s, 6H).

C048:(E)-3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-(4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as slightlyyellow crystals in 10% yield. ¹H-NMR (DMSO-d₆) δ 8.39 (d, 2H), 8.17 (d,1H), 7.89 (d, IH), 7.72-7.55 (m, 3H), 7.32-7.23 (m, 3H), 6.78 (s, 2),4.46 (t, 2H), 4.09 (s, 3H), 3.18 (t, 2H), 2.67 (s, 6H).

C049:(E)-3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-[2-(2-dimethylamino-ethoxy)-phenyl]-propenone

General procedure H gave the title compound as yellow oil in 25% yield.¹H-NMR (CDCl₃) δ 7.65 (dd, 1H), 7.60 (d, 1H), 7.47 (d, 1H), 7.47 (dt,1H), 7.31 (t, 1H), 7.22 (d, 1H), 7.1 (t, 1H), 7.05 (dt, 1H), 7.02 (m,2H), 4.17 (t, 2H), 4.10 (t, 2H), 2.75 (t, 2H), 2.73 (t, 2H), 2.36 (s,3H), 2.27 (s, 3H).

C050:(E)-3-[3-(3-Dimethylamino-propoxy)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the title compound as yellow oil in 32% yield.¹H-NMR (CDCl₃) δ 7.90 (t, 1H), 7.75 (dd, 1H), 7.44 (dd, 1H), 7.32 (t,1H), 7.22 (d, 1H), 7.17 (bs, 1H), 6.7 (dd, 1H), 6.81 (dd, 1H), 6.67 (dd,1H), 4.07 (t, 2H), 3.89 (s, 3H), 2.48 (t, 2H), 2.28 (s, 6H), 1.99 (hep,2H).

C051:(E)-1-(2,4-Dimethoxy-phenyl)-3-[3-(3-dimethylamino-propoxy)-phenyl]-propenone

General procedure H gave the title compound as yellow oil in 52% yield.¹H-NMR (CDCl₃) δ 7.77 (d, 1H), 7.65 (d, 1H), 7.49 (d, 1H), 7.30 (t, 1H),7.20 (d, 1H), 7.13 (t, 1H), 6.4 (dd, 1H), 6.58 (dd, 1H), 6.52 (d, 1H),4.06 (t, 2H), 3.92 (s, 3H), 3.89 (s, 3H),2.47 (t, 2H), 2.27 (s, 6H),1.98 (hep, 2H).

C052:(E)-3-[3-(3-Dimethylamino-propoxy)-phenyl]-1-(2-methoxy-phenyl)-propenone

General procedure H gave the title compound as yellow oil in 41% yield.¹H-NMR (CDCl₃) δ 7.62 (dd, 1H), 7.58 (d, 1H), 7.50 (dt, 1H), 7.35 (d,1H), 7.31 (t, 1H), 7.19 (d, 1H), 7.12 (t, 1H), 7.07 (dd, 1H), 7.02 (d,1H), 6.96 (dd, 1H), 4.06 (t, 2H), 3.92 (s, 3H), 2.47 (t, 2H), 2.27 (s,6H), 1.98 (hep, 2H).

C053:(E)-1-(2,5-Dimethoxy-phenyl)-3-[3-(3-dimethylamino-propoxy)-phenyl]-propenone

General procedure H gave the title compound as yellow oil in 28% yield.¹H-NMR (CDCl₃) δ 7.58 (d, 1H), 7.36 (d, 1H), 7.28 (t, 1H), 7.17-7.15 (m,2H), 7.10 (t, 1H), 7.02 (dd, 1H), 6.94 (d, 2H), 4.04 (t, 2H), 3.85 (s,3H), 3.80 (s, 3H), 2.45 (t, 2H), 2.25 (s, 6H), 2.04 (hep, 2H).

C054:(E)-3-[3-(3-Dimethylamino-propoxy)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure H gave the title compound as yellow oil in 21% yield.¹H-NMR (CDCl₃) δ 7.65 (d, 1H), 7.50 (d, 1H), 7.47 (d, 1H), 7.31 (t, 1H),7.20 (d, 1H), 7.15 (t, 1H), 6.5 (dd, 1H), 6.77 (d, 1H), 4.06 (t, 2H),3.94 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H), 2.47 (t, 2H), 2.27 (s, 6H),1.98 (hep, 2H).

C055:E)-1-(3-Dimethylaminomethyl-phenyl)-3-[3-(3-dimethylamino-propoxy)-phenyl]-propenone

General procedure H gave the title compound as yellow oil in 38% yield.¹H-NMR (CDCl₃) δ 7.97-7.92 (m, 2H), 7.79 (d, 1H), 7.59-7.57 (m, 2H),7.49 (t, 1H), 7.34 (t, H), 7.26-7.20 (m, 2H), 6.98 (dd, 1H), 4.09 (t,2H), 3.53 (s, 2H), 2.51 (t, 2H), 2.30 (s, 6H), 2.29 (s, 6H), 2.01 (m,2H).

C056:(E)-3-[4-(2-Dimethylamino-ethoxy)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as slightlyyellow crystals in 22% yield. ¹H-NMR (CDCl₃) δ 7.69 (d, 2H), 7.51 (d,1H), 7.36-7.29 (m, 2H), 7.01 (d, 2H), 6.92 (d, 1H), 6.57 (s, 2H), 4.19(t, 2H), 3,.87 (s, 3H), 3.83 (s, 3H), 379 (s, 3H), 2.89 (t, 2H), 2.40(s, 6H).

C057:(E)-3-(2,5-Dimethoxy-phenyl)-1-[2-(2dimethylamino-ethoxy)-phenyl]-propenone

General procedure H gave the title compound as yellow-brown oil in 18%yield. ¹H-NMR (CDCl₃) δ 7.93 (d, 1H), 7.62 (dd, 1H), 7.47-7.41 (m, 2H),7.17 (d, 1H), 7.04 (dt, 1H), 6.99 dd, 1H), 6.90 (d, 1H), 6.84 (d, 1H),4.17 (t, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 2.74 (t, 2H), 2.27 (s, 6H).

C058:(E)-1-[2-(2-Dimethylamino-ethoxy)-phenyl]-3-(3-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 32% yield. ¹H-NMR (CDCl₃) δ 7.73-7.70 (m, 2H), 7.62-7.43 (m,6H), 7.23 (d, 1H), 7.09 (t, 1H), 6.60 (s, 4H), 4.27 (t, 2H), 3.63 (s,2H), 2.83 (t, 2H), 2.29 (s, 12H).

C059:(E)-1-[2-(2-Dimethylamino-ethoxy)-phenyl]-3-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as brown oil in 20% yield.¹H-NMR (CDCl₃) δ 8.10 (d, 1H), 7.77-7.74 (m, 1H), 7.63 (dd, 1H),7.47-7.27 (m, 5H), 7.06-6.97 (m, 2H), 4.15 (t, 2H), 3.47 (s, 2H), 2.71(t, 2H), 2.25 (s, 6H), 2.19 (s, 6H).

C060:(E)-3-(2,4-Dichloro-phenyl)-1-[2-(2-dimethylamino-ethoxy)-phenyl]-propenone

General procedure H gave the title compound as yellow crystals in 9%yield. ¹H-NMR (CDCl₃) δ 8.00 (d, 1H), 7.77 (d, 1H), 7.72 (dd, 1H), 7.57(d, 1H), 7.50 (dt, 1H), 7.47 (d, 1H), 7.30-7.26 (m, 1H), 7.07 (dt, 1H),7.01 (d, 1H), 4.19 (t, 2H), 2.73 (t, 2H), 2.28 (s, 6H).

C061:(E)-3-(2,5-Dimethoxy-phenyl)-1-[2-(3-dimethylamino-propoxy)-phenyl]-propenone

General procedure H gave the title compound as yellow oil in 58% yield.¹H-NMR (CDCl₃) δ 7.56 (d, 1H), 7.33-7.22 (m, 3H), 7.08 (d, 1H), 6.94 (d,1H), 6.85-6.76 (m, 3H), 3.88 (t, H), 3.58 (s, 3H), 3.54 (s, 3H), 2.29(t, 2H), 1.74 (s, 6H), 1.59 (hep, 2H).

C062:(E)-3-(2,4-Dichloro-phenyl)-1-[2-(3-dimethylamino-propoxy)-phenyl]-propenone

General procedure H gave the title compound as orange oil in 34% yield.¹H-NMR (CDCl₃) δ 7.96 (d, 1H), 7.66 (dd, 1H), 7.65 (d, 1H), 7.51 (m,2H), 7.41 (d, 1H), 7.28 (dd, 1H), 7.07-6.99 (m, 2H), 4.13 (t, 2H), 2.37(t, 2H), 2.14 (s, 6H), 1.94 (hep, 2H).

C063:(E)-3-(2,5-Dimethoxy-phenyl)-1-[3-(2-dimethylamino-ethoxy)-phenyl]-propenone

General procedure I gave the title compound as yellow oil in 6% yield.¹H-NMR (CDCl₃) δ 8.08 (d, 1H), 7.60-7.53 (m, 3H), 7.39 (t, 1H), 7.17 (d,1H), 7.15 (dd, 1H), 6.94 (dd, 1H), 6.87 (d, 1H), 4.15 (t, 2H), 3.87 (s,3H), 3.83 (s, 3H), 2.77 (t, 2H), 2.35 (s, 6H).

C064:(E)-3-(2,5-Dimethoxy-phenyl)-1[4-(2-dimethylamino-ethoxy)-phenyl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 37% yield. ¹H-NMR (DMSO-d₆) δ 8.15 (d, 2H), 8.00 (d, 1H),7.89 (d, 1H), 7.54 (d, 1H), 7.07 (d, 2H), 7.04-7.01 (m, 2H), 6.57 (s,2H1), 4.26 (t, 2H), 3.84 (s, 3H),380 (s, 3H), 2.92 (t, 2H), 2.41 (s,6H).

C065:(E)-3-[4-(2Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-ethoxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 67%yield. ¹H-NMR (DMSO-d₆) δ 7.98 (d, 1H), 7.85 (d, 1H), 7.69-7.61 (m, 2H),7.55-7.49 (m, 2H), 7.29 (bs, 2H), 7.05 (t, 1H), 6.96 (bs, 1H), 4.18-4.11(m, 4H), 2.65 (t, 2H), 2.33 (5, 6H), 2.19 (s, 6H), 1.33 (t, 3H).

C066:(E)-3-[4-(2-Dimethylaminoethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-ethoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 34% yield. ¹H-NMR (CDCl₃) δ 7.85 (d, 1H), 7.71 (d, 11H),7.55-7.46 (m, 3H), 7.39 (dd, 1H), 7.30-7.13 (m, 6H), 7.03 (t, 1H), 6.59(s, 3H), 4.27 (t, 2H), 4.11 (q, 2H), 2.94 (t, 2H), 239 (s, 6H), 2.25 (s,3H); 1.26 (t, 3H).

C067:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1(2-isopropoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 26% yield. ¹H-NMR (DMSO-d₆) 6 7.99 (d, 11H), 7.87 (d, 1H),7.70 (dd, 1H), 7.60 (d, 1H), 7.54-7.48 (m, 2H), 7.29 (bs, 2H), 7.19 (bd,2H), 7.03 (t, 1h), 6.97 (bs, 1H), 6.59 (s, 3H), 4.8 (m, 1H), 4.25 (t,2H), 2.90 (t, 2H), 2.37 (s, 6H), 2.33 (s, 6H), 1.31 (s, 3H), 1,29 (s,3H)

C068: (E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-[2-(1-hydroxy-ethylamino)-phenyl]-propenone

General procedure H gave the fumarate of the title compound as orangepowder in 5% yield. ¹H¹-NMR (DMSO-d₆) δ 9.28 (t, 1H), 8.19-8.10 (m, 2H),7.96 (d, 1H), 7.89 (d, 1H), 7.42-7.24 (m, 6H), 7.19 (d, 1H), 6.81 (d,1H), 6.59 (t, 1H), 6.59 (s, 2H), 4.26 (t, 2H), 3.28 (q, 2H), 2.86 (t,2H), 2.36 (s, 6H), 2.27 (s, 3H).

C069:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[2-(2-hydroxy-ethylamino)-phenyl]-propenone

General procedure H gave the title compound as orange powder in 39%yield. ¹H-NMR (DMSO-d₆) δ 9.27 (t, 1H), 8.21-8.16 (m, 2H), 8.10 (d, 1H),7.95 (d, 1H), 7.66 (dd, 1H), 7,41 (t, 1H), 7.33 (bs, 2H), 7.20 (d, 1H),6.98 (bs, 1H), 6.82 (d, 1H), 6.64(t, 1H), 4.89 (t, 1H), 4.22 (t, 2H),3.66 (q, 2H), 3.29 (t, 2H), 2.75 (t, 2H), 2.35 (s, 6H), 2.27 (s, 6H).

C070:(E)-3-[3-(2-Dimethylamino-ethoxy)-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as brownish oil in 54%yield. ¹H-NMR (DMSO-d₆) δ 7.48-7.37 (m, 4H), 7.33-7.31 (m, 2H),7.28-7.24 (m, 3H), 6.98 (dt, 1H), 4.08 (t, 2H), 3.51 (s, 2H), 2.61 (t,2H), 2.20 (s, 6H), 2.02 (s, 6H).

C071:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[3-(3-dimethylamino-propoxy)-phenyl]-propenone

General procedure H gave the title compound as yellow oil in 55% yield.¹H-NMR (DMSO-d₆) δ 7.49-7.38 (m, 4H), 7.32 (d, 1H), 7.30-7.28 (m, 2H),7.24 (bs, 2H), 6,97 (dt, 1H), 4.03 (t, 2H), 3.51 (s, 2H), 2.34 (t, 2H),2.13 (s, 6H), 2.02 (s, 6H), 0.83 (p, 2H).

C072:3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(4-fluoro-phenyl)-propan-1-one

General procedure N gave the title compound as colourless oil in 33%yield. ¹H-NMR (CDCl₃) δ 8.05 (m, 2H), 7.43 (m, 2H), 7.2-7.08 (m, 4H),7.00 (bs, 1H), 6.94 (bd, 1H), 4.18 (t, 2H), 3.32 (t, 2H), 3.12 (t, 2H),2.80 (t, 2H), 2.40 (s, 6H), 2.35 (s, 6H).

C073:3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propan-1-one

General procedure N gave the fumarate of the title compound as whitecrystals in 39% yield. ¹H-NMR (DMSO-d₆) δ 7.47 (d, 1H), 7.45-7.30 (m,3H), 7.25-7.10 (m, 6H),7.02 (d, 1H), 6.60 (s, 5H), 4.15 (t, 2H), 3.53(bs, 2H), 3.15 (t, 2H), 2.90 (t, 2H), 2.80 (t, 2H), 2.33 (s, 6H), 2.20(s, 3H), 2.06 (s, 6H).

C074:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[2-(2-dimethylamino-ethylamino)-phenyl]-propenone

General procedure H gave the fumarate of the title compound as orangepowder in 45% yield. ¹H-NMR (DMSO-d₆) δ 9.18 (t,1H), 8.22-8.10 (m,3H),7.96 (d,1H), 7.68 (dd,1H), 7.43 (t,1H), 7.33 (s,2H), 7.21 (d,1H), 6.98(s, 1H), 6.85 (d, 1H), 6.67 (t, 1H), 6.58 (s, 5), 4.31 (t, 2H),3.50-3.35 (m, 2H), 3.01 (t,2H), 2.76 (t,2H), 2.45 (s,6H), 2.42 (s, 6H),2.35 (s, 6H).

C075:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[3-(2-dimethylamino-ethylamino)-phenyl]-propenone

General procedure H gave the fumarate of the title compound as orangepowder in 34% yield. ¹H-NMR (DMSO-d₆) δ 8.13 (d, 1H), 8.08-7.95 (m, 2H),7.70 (dd, 1H), 7.42 (d, 1H), 7.37-7.18 (m, 5H), 6.97 (s, 1H), 6.90 (dd,1H), 6.58 (s, 4H), 4.31 (t, 2H), 3.50-3.35 (m, 2H), 2.96 (t, 2H), 2.88(t, 2H), 2.41 (s, 6H), 2.35 (s, 6H).

C076:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-{2-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 35% yield. ¹H-NMR (DMSO-d₆) δ 7.98 (d, 1H), 7.65 (d, 1H),7.52 (dd, 1H), 7.37 (d, 1H), 7.30-7.30 (m, 2H), 7.08 (s, 2H), 7.00-6.92(m, 2H), 6.80 (s, 1H), 6.74 (s, 1H), 6.33 (s, 4H). 4.05 (t, 2H), 3.05(t, 2H), 2.70 (t, 2H), 2.88 (t, 2H), 2.15 (s, 6H), 2.10 (s, 6H), 2.05(s, 6H).

C077:(E)-1-(2-Butoxy-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 66% yield. ¹H-NMR (DMSO-d₆) δ 8.00 (d, 1H), 7.88 (d, 1H),7.69 (dd, 1H), 7.60 (d, 1H), 7.56-7.47 (m, 2H), 7.30 (s, 2H), 7.22-7.13(m, 2H), 7.05 (t, 1H), 6.96 (s, 1H), 6.59 (s, 3H), 4.28 (t, 2H), 4.09(t, 2H), 2.98 (t, 2H), 2.42 (s, 6H), 2.32 (s, 6H), 1.74-1.60 (m, 2H),1.43-1.28 (m, 2H), 0.70 (t, 3H).

C078:(E)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-fluoro-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowpowder in 83% yield. ¹H-NMR (DMSO-d₆) δ 8.05 (d, 1H), 7.92 (d, 1H),7.80-7.60 (m, 3H), 7.43-7.30 (m, 3H), 7.20 (d, 1H), 6.97 (s, 1H), 6.59(s, 2H), 4.25 (t, 2H), 2.90 (t, 2H), 2.35 (s, 6H), 2.3 (s, 6H).

C079:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-y]-1-(3-fluoro-phenyl)-propenone

General procedure H gave, the fumarate of the title compound as yellowpowder in 48% yield. ¹H-NMR (DMSO-d₆) δ 8.18 (d, 1H), 8.10 (s, 2H), 8.02(d, 1H), 7.93 (dt, 1H), 7.75-7.60 (m, 2H), 7.53 (td, 1H), 7.33 (s, 2H),7.22 (d, 1H), 6.98 (s, 1H), 6.58 (s, 1H), 4.2 (t, 2H), 2.85 (t, 2H),2.35 (s, 12H).

C080:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(4-fluoro-phenyl)-propenone

General procedure H gave the title compound as yellow powder in 82%yield. ¹H-NMR (DMSO-d₆) δ 8.30-8.20 (m, 2H), 8.18-8.01 (m, 3H), 7.68(dd, 1H), 7.41 (t, 2H), 7.32 (s, 2H), 7.20 (d, 1H), 6.97 (s, 1H), 4.21(t, 2H), 2.73 (t, 2H), 2.34 (s, 6H), 2.27 (s, 6H).

C081:(E)-1-(2-Bromo-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 58% yield. ¹H-NMR (DMSO-d₆) δ 8.07 (d, 1H), 7.78-7.63 (m,3H), 7.58-7.38 (m, 4H), 7.33 (s, 2H), 7.17 (d, 1H), 6.96 (s, 1H), 6.59(s, 2H), 4.20 (t, 2H), 2.78 (t, 2H), 2.33 (s, 6H), 2.27 (s, 6H).

C082:(E)-1-(3-Bromo-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 23% yield. ¹H-NMR (DMSO-d₆) δ 8.25 (s, 1H), 8.22-8.01 (m,4H), 7.87 (d, 1H), 7.72 (dd, 1H), 7.55 (t, 1H), 7.33 (s, 2H), 7.22 (d,1H), 6.98 (s, 1H), 6.59 (s, 3H), 4.31 (t, 2H), 3.00 (t, 2H), 2.45 (s,6H), 2.34 (s, 6H).

C083:(E)-1-(4-Bromo-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone

General procedure H gave the title compound as yellow powder in 93%yield. ¹H-NMR (DMSO-d₆) δ 8.16-8.05 (m, 5H), 7.79 (d, 2H), 7.69 (dd,1H), 7.32 (s, 2H), 7.20 (d, 1H), 6.97 (s, 1H), 4.20 (t, 2H), 2.71 (t,2H), 2.33 (s, 6H), 2.25 (s, 6H).

C084:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-hydroxy-phenyl)-propenone

General procedure H gave the title compound as yellow powder in 40%yield. ¹H-NMR (DMSO-d₆) δ 12.68 (s, 1H), 8.30-8.20 (m, 2H), 8.20-8.10(m, 2H), 7.72 (dd, 1H), 7.59 (t, 1H), 7.32 (s, 2H), 7.21 (d, 1H),7.10-6.95 (m, 3H), 4.23 (t, 2H), 2.75 (t, H), 2.35 (s, 6H), 2.28 (s,6H).

C085:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-hydroxy-phenyl)-propenone

General procedure H gave the title compound as yellow, crystals in 87%yield. ¹H-NMR (DMSO-d₆) δ 9.75 (s, 1H), 8.15-7.95 (m, 3H), 7.72-7.55 (m,2H), 7.44 (s, 1H), 7.40-7.25 (m, 3H), 7.20 (d, 1H), 7.05 (dd, 1H), 6.95(s, 1H), 4.22 (t, 2H), 2.74 (t, 2H), 2.35 (s,6H), 2.27 (s, 6H).

C086:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(4-hydroxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 48% yield. ¹H-NMR (DMSO-d₆) δ 8.15-7.93 (m, 5H), 7.67 (dd,1H), 7.32 (s, 2H), 7.19 (d, 1H), 6.97 (s, 1H), 6.91 (d, 2H), 6.57 (s,1H), 4.25 (t, 2H), 2.87 (t, 2H), 2.36 (s, 6H), 2.33 (s, 6H).

C087:(E)-1-(4-Cyclohexyl-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone

General procedure H gave the title compound as yellow crystals in 59%Yield. H-NMR (DMSO-d₆) δ 8.15-7.97 (m, 5H), 7.67 (dd, 1H), 7.40 (d, 2H),7.32 (s, 2H), 7.18 (d, 1H), 6.96 (s, 1H), 4.20 (t, 2H), 2.73 (t, 2H),2.65-2.52 (m, 1H), 2.33,(s, 6H) 2.25 (s, 6H), 1.85-1.63 (m, 5H),1.52-1.12 (m, 5H).

C088:N-(3-{3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-(E)-acryloyl}-phenyl)-acetamide

General procedure H gave the title compound as yellow crystals in 64%yield. ¹H-NMR (DMSO-d₆) δ 10.15 (s, 1H), 8.23 (s, 1H), 8.10 (d, 1H),8.02 (d, 2H), 7.92-7.82 (m, 2H), 7.69 (dd, 1H), 7.50 (t, 1H), 7.32 (s,2H), 7.21 (d, 1H), 6.96 (s, 1H), 4.1 (t, 2H), 2.74 (t, 2H), 2.32 (s,6H), 2.25 (s, 6H), 2.07 (s, 3H).

C089:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 59% yield. ¹H-NMR (DMSO-d₆) δ 8.14 (m, 2H), 8.10-8.01 (m,3H), 7.70 (dd, 1H), 7.65 (dt, 1H), 7.57 (t, 1H), 7.33 (bs, 2H), 7.22 (d,11H), 6.98 (bs, 1H), 6.57 (s, 4H), 4.34 (t, 2H), 3.77 (s, 2H), 3.05 (t,2H), 2.48 (s, 6H), 2.35 (s, 6H), 2.34 (s, 6H).

C090:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 38% yield. ¹H-NMR (DMSO-d₆) δ 8.23 (dd, 1H), 8.14-8.11 (m,2H), 8.08 (d, 1H), 8.02 (d, 1H), 7.70 (dd, 1H), 7.34 (bs, 2H), 7.20 (t,2H), 6.98 (bs, 2H), 6.56 (s, 4H), 4.31 (t, 2H), 3.92 (s, 3H), 3.74 (s,2H), 2.97 (t, 2H), 2.42 (s, 6H), 2.37 (s, 6H), 2.35 (s, 6H).

C091:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as off-white crystals in 58%yield. ¹H-NMR (DMSO-d₆) δ 8.01 (d, 1H), 7.66 (dd, 1H), 7.59 (d, 1H),7.46-7.36 (m, 5H), 7.32 (bs, 2H), 7.14 (d, 1H), 6.96 (bs, 1H), 4.12 (t,2H), 3.50 (S; 2H, 2.59 (t, 2H), 2.33 (s, 6H), 2.11 (s, 6H), 2.03 (s,6H).

C092:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-4-methoxy-phenyl)-propenone

General procedure H gave the title compound as off-white crystals in 48%yield. ¹H-NMR (DMSO-d₆) δ 8.01 (d, 1H), 7.68-7.63 (m, 2H), 7.51 (d, 1H),7.47 (d, 1H), 7.32 (bs, 2H), 7.15 (d, 1H), 7.04 (d, 1H), 6.96 (bs, 1H),6.92 (dd, 1H, 4.15 (t, 2H), 3.82 (s, 3H), 3.55 (s, 2H), 2.63 (t, 2H),2.33 (s, 6H), 2.15 (s, 6H), 2.07 (s, 6H).

C093:(E)-1-(2-Amino-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 53% yield. ¹H-NMR (DMSO-d₆) δ 8.18-8.05 (m, 3H), 7.94 (d,1H), 7.66 (dd, 1H), 7.45-7.23 (m, 5H), 7.19 (d, 1H), 6.97 (s, 1H), 6.80(d, 1H), 6.64-6.53 (m, 2H), 4.25 (t, 2H), 2.84 (t, 2), 2.33 (s, 6H).

C094:(E)-1-(4-Amino-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 20% yield. ¹H-NMR (DMSO-d₆) δ 8.17-8.02 (m, 2H), 8.02-7.90(m, 3H), 7.68 (dd, 1H), 7.37 (s, 2H), 7.23 (d, 1H), 7.02 (s, 1H), 6.66(d, 2H), 6.63 (s, 2H), 6.17 (s, 2H), 4.30 (t, 2H), 2.95 (t, 2H), 2.43(s, 6H), 2.38 (s, 6H).

C095:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 32% yield. ¹H-NMR (DMSO-d₆) δ 8.06 (dd, 1H), 7.80-7.60 (m3H), 7.53-7.41 (m, 1H), 7.39-7.22 (m, 3H), 7.17 (t, 1H), 7.04-6.85 (m,2H), 6.59 (s, 2H), 4.20 (t, 2H), 2.70 (t, 2h), 2.31 (s, 6H), 2.20 (s,6H), 2.05 (s, 6H).

C096:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-[4-hydroxy-2-(4-methyl-piperazin-1-yl)-phenyl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 6% yield. ¹H-NMR (DMSO-d₆) δ 8.10-7.93 (m, 5H), 7.57 (dd,1H), 7.43-7.35 (m, 2H), 7.21 (d, 1H), 7.17 (d, 1H), 7.08 (t, 1H), 6.95(d, 1H), 6.63 (s, 4H), 4.40 (t, 2H), 3.80 (s, 3H), 3.74 (s, 2H), 3.18(t, 2H), 2.78 (s, br, 4H), 2.65 (s, br, 4H), 2.60 (s, 6H), 2.44 (s, 3H).

C097:(E)-3-[2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as off-whitepowder in 35% yield. ¹H-NMR (DMSO-d₆) δ 8.16 (d, 2H), 8.02 (dd, 3H),7.60-7.57 (m, 1H), 7.51-7.38 (m, 4H), 7.23 (d, 1H), 7.07 (d, 2H), 6.59(s, 2H), 4.31 (t, 2H), 3.86 (s, 3H), 2.95 (t, 2H), 2.42 (s, 6H).

C098:(E)-3-[2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowpowder 10% yield. ¹H-NMR (DMSO-d₆) δ 7.94 (d, 1H), 7.87-7.80 (m, 2H),7.66 (dd, 1H), 7.59-7.37 (m, 5H), 7.24 (d, 1H), 6.99-6.89 (m, 2H), 6.59(s, 3H), 4.32 (t, 2H), 3.86 (s, 3H), 2.99 (t, 2H), 2.42 (s, 6H).

C099:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[4-hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone

General procedure H gave the title compound as off-white powder in 58%yield. ¹H-NMR (DMSO-d₆) δ 7.99 (d, 1H), 7.66 (dd, 1H), 7.57 (d, 1H),7.43-7.35 (m, 4H), 7.14 (d, 1H), 6.96 (bs, 1H), 4.12 (t, 2H), 3.53 (s,2H), 2.58 (t, 2H) 2.50 (t, 4H), 2.33 (s, 6H), 2.24 (bs, 4H), 2.11 (s,6H), 1.99 (s, 3H).

C100:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[4-(2-dimethylamino-ethylamino)-phenyl]-propenone

General procedure H gave the oxalate of the title compound as yellowcrystals in 27% yield. ¹H-NMR (DMSO-d₆) δ 8.20 (d, 1H), 8.05-8.02 (m,4H), 7.69 (dd, 1H), 7.35 (bs, 2H), 7.22 (d, 1H), 6.99 (bs, 1H), 6.93(bs, 1H), 6.73 (d, 2H), 4.47 (t, 2), 3.56-3.51 (m, 4H), 3.20 (t, 2H),2.83 (s, 6H), 2.78 (s, 6H), 2.36 (s, 6H).

C101:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[2-(2-dimethylamino-ethoxy)-phenyl]-propenone

General procedure H gave the oxalate of the title compound as yellowpowder in 14% yield. ¹H-NMR (DMSO-d₆) δ 8.09 (d, 1H), 7.82 (d, 1H), 7.73(dd, 1H), 7.58-7.49 (m, 3H), 7.33 (bs, 2H), 7.24-7.20 (m, 2H), 7.12 (t,1H), 6.98 (bs, 1H), 4.44-443 (m, 4H), 3.46 (t, 2H), 3.36 (t, 2H), 2.75(s, 6H), 2.65 (s, 6H), 2.33 (s, 6H).

C102:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-hexyloxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 33% yield ¹H-NMR (DMSO-d₆) δ 8.17 (d, 1H). 8.06 (bs, 2H).7.75 (d, 1H). 7.70 (dd, 1H). 7.59 (bs, 1H). 7.47 (t, 1H). 7.33 (bs, 2H).7.24-7.19 (m, 2H). 6.97 (s, 1H). 6.59 (s, 2H). 4.31 (t, 2H). 4.04 (t,2H). 2.99 (t, 2H). 2.44 (s, 6H). 2.34 (s, 6H). 1.73 (p, 2H). 1.43 (p,2H). 1.34-1.29 (m, 4H). 0.87 (t, 3H).

C103:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[3-(4-methyl-piperazin-1-yl)-phenyl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 34% yield. ¹H-NMR (DMSO-d₆) δ 8.16 (d, 1H), 8.04 (d, 2H),7.72 (dd, 1H), 7.63 (d, 1H), 7.55 (bs, 1H), 7.42 (t, 1H), 7.34 (s, 2H),7.27 (dd, 1H), 7.22 (d, 1H), 6.98 (s, 1H), 6.67 (d, 1H), 6.59 (s, 2H),4.32 (t, 2H), 3.33-3.27 (m, 4H), 3.04 (t, 2H), 2.69-2.64 (m, 4H). 2.47(s, 6H), 2.36 (s, 3H), 2.34 (s, 6H).

C104:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[2-(3-dimethylamino-propoxy)-phenyl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 57% yield. ¹H-NMR (DMSO-d₆) δ 8.06 (d, 1H), 7.82 (d, 1H),7.69 (dd, 1H), 7.57 (d, 1H), 7.51 (d, 1H), 7.47 (dd, 1H), 7.31 (s, 2H),7.18 (q, 2H), 7.08 (t, 1H), 6.96 (s, 1H),6.55 (s, 4H), 4.29 (t, 2H),4.13 (t, 2H), 2.93 (t, 2H),2.74 (t, 2H), 2.37 (s, 6H), 2.33 (s, 6H),2.25 (s, 6H), 1.96 (p, 2H).

C105:(E)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-fluoro-4-hydroxy-phenyl)-propenone

General procedure H gave the title compound as yellow powder in 26%yield. ¹H-NMR (DMSO-d₆) δ 10.82 (bs, 1H), 8.99 (d, 2H), 7.90 (bd, 1H),7.78-7.66 (m, 3H), 7.33 (s, 2H), 7.19 (d, 1H), 6.97 (bs, 1H), 6.74 (dd,1H), 6.66 (dd, 1H), 4,20 (t,2H), 2.72 (t, 2H), 2.33 (s, 6H), 2.33 (s,6H).

C106:(E)-1-(6-Amino-benzo[1,3]dioxol-5-yl)-3-[4-(2-dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-propenone

General procedure H gave the fumarate of the title compound as orangepowder in 60% yield. ¹H-NMR (DMSO-d₆) δ 8.13 (d, 1H), 8.04 (d, 1H), 0.91(d, 1H), 7.76-7.67 (m, 3H), 7.64 (dd, 1H), 7.33 (s, 2H), 7.18 (d, 1H),6.98 (s, 2H), 6.60 (s, 2H), 6.37 (s, 1H), 5.97 (s, 2H), 4.26 (t, 2H),2.90 (t, 2H), 2.39 (s, 6H), 2.35 (s, 6H).

C107:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-phenyl-propenone

General procedure H gave the title compound as yellow powder in 35%yield. ¹H-NMR (DMSO-d₆) δ 8.22-8.12 (m, 3H), 8.05 (d, 1H), 7.82-7.62 (m,3H), 7.61-7.55 (m, 2H), 7.40-7.32 (m, 2H), 7.21 (d, 1H), 6.98 (s, 1H),4.23 (t, 2H), 2.74 (t, 2H), 2.35 (s, 6H), 2.27 (s, 6H).

C108:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowfoam in 14% yield. ¹H-NMR (DMSO-d₆) δ 8.07-7.97 (m, 4H), 7.90 (d, 1H),7.37 (dd, 1H), 7.27-7.24 (m, 4H), 7.20 (d, 1H), 6.89 (d, 1H), 6.59 (s,4H), 4.29 (t, 2H), 3.81 (br s, 2H), 2.94 (br t, 2H), 2.41 (d, 6H), 2.37(s, 6H), 2.27 (s, 3H).

C109:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowpowder in 32% yield. ¹H-NMR (DMSO-d₆) δ 8.22 (dd, 1H), 8.11 (d, 1H),8.03 (dd, 2H), 7,90 (d, 1H), 7.39 (dd, 1H), 7.32-7.25 (m, 4H), 7.21 (d,1H), 7.14 (d, 1H), 6.57 (s, 4H), 4.30 (t, 2H), 3.90 (s, 3H), 3.69 (s,2H), 2.95 (t, 2H), 2.41 (s, 6H), 2.33 (s, 6H), 2.27 (s, 3H).

C110:2-Dimethylamino-N-(3-{3-[4-(2-dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-(E)-acryloyl}-phenyl)-acetamide

General procedure H gave the fumarate of the title product as yellowpowder in 21% yield. ¹H-NMR (DMSO-d₆) δ 10.04 (br s, 1H), 8.33 (t, 1H),8.09 (d, 1H), 7.96 (d, 1H), 7.96 (d, 1H), 4.35 (t, 2H), 7.92-7.86 (m,2H), 7.49 (t, 1H), 7.41 (dd, 1H), 7.33-7.20 (m, 5H), 5.59 (s, 4H), 4.35(t, 2H), 3.20 (s, 2H), 3.07 (t, 2H), 2.49 (s, 6H), 2.34 (s, 6H), 2.27(s, 3H).

C111:(E)-3-[4-(4-Dimethylamino-butoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow oil in 25% yield.¹H-NMR (CDCl₃) δ 7.65 (d, 1H), 7.53 (d, 1H), 7.44-7.38 (m, 3H), 7.33(dd, 1H), 7.30-7.22 (m, 5H), 7.13 (d, 1H), 6.95 (d, 1H), 4.07 (t 2H),3.57 (s, 2H), 2.33 (t, 2H), 2.30 (s, 3H), 2.25 (s, 6H), 2.16 (s, 6H),1.83 (p, 2H), 1.61 (p, 2H).

C112:(E)-3-[2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-5-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 40% yield. ¹H-NMR (DMSO-d₆) δ 7.81 (d, 1H), 7.81 (d, 1H),7.59-7.36 (m, 8H), 7.20 (t, 2H), 6.58 (s, 4H), 4.28 (t, 2H), 3.85 (s;3H), 3.71 (s, 2H), 2.90 (t, 2H), 2.35 (s, 6H), 2.34 (s, 6H).

C113:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-5-methoxy-phenyl)-propenone

General procedure H gave the hydrochloride of the title product asyellow powder in 8% yield. ¹H-NMR (DMSO-d₆) δ 11.10 (br, 1H), 10.95 (br,1H), 7.86 (d, 1H), 7.80-7.68 (m, 3H), 7.46 (d, 1H), 7.44 (dd, 1H),7.31-7.20 (m, 6H), 4.55 (t, 2H), 4.26 (d, 2H), 3.86 (s, 3H), 3.61-3.53(m, 2H), 2.83 (d, 6H), 2.66.(d, 6H), 2.26 (s, 3H).

C114:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-imethylaminomethyl-4-methoxy-phenyl)-propenone

General procedure H gave the hydrochloride of the title product asyellow powder in 22% yield. ¹H-NMR (DMSO-d₆) δ 11.29 (br, 1H), 9.56 (br,1H), 8.29 (d, 1H), 8.08 (d, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.46 (dd,1H), 7.40 (d, 1H), 7.33-7.23 (m, 5H), 7.17 (dd, 1H), 4.59 (t, 2H), 4.44(d, 2H), 3.91 (s, 3H), 3.62-3.56 (m, 2H), 2.87 (d, 6H), 2.80 (d, 6H),2.27 (s, 3H).

C115:(E)-3-[5-(1,1-Dimethyl-allyl)-2-(2-dimethylamino-ethoxy)-phenyl]-1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-propenone

General procedure H gave the fumarate of the title product as whitecrystals in 41% yield. ¹H-NMR (DMSO-d₆) δ 8.11 (d, 2H), 8.01 (d, 1H),7.92 (d, 1H), 7.74 (d, 1H), 7.34 (dd, 1H), 7.17 (d, 2H), 7.07 (d, 1H),6.60 (s, 2H), 6.06 (dd, 1H), 5.65 (br, 1H),5.06 (dd, 1H), 5.01 (s, 1H),3.78-3.70 (m, 1H), 4.25-4.18 (m, 2H), 2.85-2.72 (m, 2H), 2.32 (s, 6H),1.40 (s, 6H).

C116:3-[5-(1,1-Dimethyl-allyl)-2-(2-dimethylamino-ethoxy)-phenyl]-1-(4-hydroxy-phenyl)-propenone

The fumarate of3-[5-(1,1-Dimethyl-allyl)-2-(2-dimethylamino-ethoxy)-phenyl]-1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-propenonewas suspended in H₂O and MeOH was added to give a solution. Stirred at55° C. for 72 hr, until the deprotection was complete according to TLC.Co-evaporation of the solvent with MeCN gave a yellow solid.Recrystallisation from H₂O gave the fumarate of the title compound asyellow crystals in 51% yield. LCMS and ¹H-NMR showed a mixture of E- andZ- isomers in approximately 1:1 ratio. ¹H-NMR (DMSO-d₆) δ 8.03 (d, 2H),7.97 (d, 1H), 7.89 (d, 1H), 7.72 (d, 1H), 7.69 (s, 1H), 7.66 (s, 2H),7.33 (dd, 1H), 7.11 (dd, 1H), 7.06 (d, 1H), 7.05 (s, 2H), 6.90 (d, 2H),6.81 (d, 1H), 6.73 (d, 2H), 6.58)s, 4H), 6.06 (dd, 1H), 5.89 (dd, 1H),5.03 (dd, 1H), 4.86 (dd, 1H), 4.54 (t, 1H), 4.20 (t, 2H), 3.97 (t, 1H),3.72 (t, 2H), 2.86 (t, 2H), 2.36 (s, 6H), 2.29 (t, 2H), 2.11 (s, 6H),1.40 (s, 6H), 1.22 (s, 6H).

C117:(E)-3-[6-(2-Dimethylamino-ethoxy)-2,3,3-trimethyl-2,3-dihydro-benzofuran-5-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 55% yield. ¹H-NMR (DMSO-d₆) δ 7.70 (s, 1H), 7.62 (d, 1H),7.50-7.40 (m, 4H), 7.18 (d, 1H), 6.59 (s, 4H), 6.55 (s, 1H), 4.44 (q,1H), 4.09 (t, 2H), 3.62 (s, 2H), 2.74 (t, 2H), 2.23 (s, 6H), 2.17 (s,6H), 1.31 (d, 3H), 1.30 (s, 3H), 1.06 (s, 3H).

C118:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-propenone

General procedure H gave the fumarate of the title product as browncrystals in 44% yield. ¹H-NMR (DMSO-d₆) δ 7.78 (d, 1H), 7.68 (d, 1H),7.50-7.43 (m, 3H), 7.41-7.35 (m, 2H), 7.35 (d, 1H), 7.30-7.20 (m, 4H),7.15 (d, 1H), 6.54 (s, 6H), 4.22 (t, 2H), 3.64 (s, 2H), 2.81 (m, 4H),2.54 (t, 2H), 2.44 (s, 6H), 2.28 (s, 6H), 2.25 (s, 3H), 2.01 (s, 3H).

C119:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-pyrrolidin-1-ylmethyl-phenyl)-propenone

General procedure H gave the fumarate of the title product as yellowcrystals in 23% yield. ¹H-NMR (DMSO-d₆) δ 7.77 (d, 1H), 7.68 (d, 1H),7.54 (d, 1H), 7.51-7.47 (m, 2H), 7.44-7.34 (m, 3H), 7.30-7.20 m, 4H),7.16 (d, 1H), 6.58 (s, 4H), 4.24 (t, 2H), 3.87 (s, 2H), 2.86 (t, 2H),2.57 (br t, 4H), 2.31 (s, 6H), 2.24 (s, 3H), 1.64 (br p, 4H).

C120:(E)-1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl}-3-[4-(2-dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-propenone

General procedure H gave the title product as yellow oil in 17% yield.¹H-NMR (DMSO-d₆) δ 7.70 (d, 1H), 7.60 (d, 1H), 7.49 (d, 1H), 7.45-7.20(m, 9H), 7.13 (d, 1H), 4.12 (t, 2H), 3.61 (s, 2H), 2.58 (t, 2H), 2.24(s, 3H), 2.11 (s, 6H), 1.86 (s, 3H), 0.98 (s, 9H).

C121:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-trifluoromethoxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow crystals in 43%yield. ¹H-NMR (DMSO-d₆) δ 7.86 (d, 1H), 7.61-7.56 (m, 2H), 7.51 (d, 1H),7.51 (d, 1H), 7.49-7.35 (m, 6H), 7.27 (d, 1H), 7.18 (d, 1H), 4.14 (t,2H), 3.49 (s, 2H), 2.59 (t, 2H), 2.11 (s, 6H), 2.01 (s, 6H).

C122:(E)-3-[2′-tert-Butoxymethyl-4-(2-dimethylamino-ethoxy)-biphenyl-3-y]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as green oil in 28% yield.¹H-NMR (DMSO-d₆) δ 7.80 (d, 1H), 7.56 (d, 1H), 7.46-7.40 (m, 4H),7.37-7.32 (m, 4H), 7.30-7.26 (m, 1H), 7.23 (d, 1H), 7.15 (d, 1H), 4.24(s, 2H), 4.13 (t, 2H), 3.47 (s, 2H), 2.59 (t, 2H), 2.12 (s, 6H), 2.01(s, 6H), 1.10 (s, 9H).

C123:(E)-3-[4-(Z-Dimethylaminoethoxy)-2′,5′-dimethoxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow crystals in 27%yield. ¹H-NMR (CDCl₃) δ 7.78 (d, 1H), 7.64 (d, 1H), 7.54 (dd, 1H),7.49-7.32 (m, 4H), 7.16 (d, 1H), 6.97-6.84 (m, 4H), 4.15 (t, 2H), 3.83(s, 3H), 3.78 (s, 3H), 3.61 (s, 2H), 2.73 (t, 2H), 2.27 (s, 6H), 2.18(s, 6H).

C124:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′,4′-dimethoxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as green crystals in 36%yield. ¹H-NMR (DMSO-d₆) δ 7.75 (d, 1H), 7.56 (d, 1H), 7.48-7.35 (m, 5H),7.24 (d, 1H), 7.23 (d, 1H), 7.08 (d, 1H), 6.66 (d, 1H), 6.60 (dd, 1H),4.11 (t, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.50 (s, 2H), 2.58 (t, 2H),2.11 (s, 6H), 2.02 (s, 6H).

C125:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′,4′,6′-trimethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow oil in 52% yield.¹H-NMR (DMSO-d₆) δ 7.60 (d, 1H), 7.52 (br s, 1H), 7.46-7.31 (m, 4H),7.26 (d, 1H), 7.12 (br s, 2H), 6.92 (br s, 2H), 4.12 (t, 2H), 3.49 (s,2H), 2.59 (t, 2H), 2.26 (s, 3H), 2.11 (s, 6H), 2.02 (s, 6H), 1.95 (s,6H).

C126:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methoxymethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as green crystals in 21%yield. ¹H-NMR (DMSO-d₆) δ 7.76 (d, 1H), 7.58 (d, 1H), 7.51-7.30 (m, 9H),7.25 (d, 1H), 7.15 (d, 1H), 4.30 (s, 2H), 4.13 (t, 2H), 3.49 (s, 2H),3.24 (s, 3H), 2.60 (t, 2H), 2.12,(s, 6H), 2.02 (s, 6H).

C127:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′,6′-dimethoxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as green crystals in 84%yield. ¹H-NMR (DMSO-d₆) δ 7.57 (d, 1H), 7.54 (d, 1H), 7.45-7.20 (m, 7H),7.15 (d, 1H), 7.06 (d, 1H), 6.75 (s, 1H), 6.73 (s, 1H), 4.11 (t, 2H),3.67 (s, 6H), 3.49 (s, 2H), 2.59 (t, 2H), 2.12 (s, 6H), 2.02 (s, 6H).

C128:(E)-3-[2′-Chloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow oil in 18% yield.¹H-NMR (DMSO-d₆) δ 7.82 (d, 1H), 7.48 (d, 1H), 7.58-7.54 (m, 1H),749-7.35 (m, 8H), 7.28 (d, 1H), 7.17 (d, 1H), 4.15 (t, 2H), 3.50 (s,2H), 2.60 (t, 2H), 2.12 (s, 6H), 2.02 (s, 6H).

C129:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methylsulfanyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow oil in 25% yield.¹H-NMR (DMSO-d₆) δ 7.73 (d, 1H), 7.57 (d, 1H), 7.45-7.31 (m, 7H), 7.23(d, 1H), 7.24-7.20 (m, 2H), 7.13 (d, 1H), 4.13 (t, 2H), 3.49 (s, 2H),2.59 (t, 2H), 2.37 (s, 3H), 2.12 (s, 6H), 2.02 (s, 6H).

C130:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-trifluoromethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow oil in 43% yield.¹H-NMR (DMSO-d₆) δ 7.83 (d, 1H), 7.75-7.68 (m, 2H), 7.61 (t, 1H), 7.56(d, 1H), 7.47-7.30 (m, 6H), 7.23 (d, 1H), 7.14 (d, 1H), 4.14 (t, 2H),3.49 (s, 2H), 2.60 (t, 2H), 2.12 (s, 6H), 2.02 (s, 6H).

C131:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-hydroxy-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave, the title product as yellow crystals in 14%yield. ¹H-NMR (DMSO-d₆) δ 9.55 (br, 1H), 7.87 (d, 1H), 7.59 (dd, 1H),7,47 (d, 1H), 7.47-7.35 (m, 4H), 7.30 (dd, 1H), 7.22 (d, 1H), 7.15 (td,1H), 7.11 (d, 1H), 6.93 (dd, 1H), 6.87 (td, 1H), 4.12 (t, 2H), 3.49 (s,2H), 2.59 (t, 2H), 2,12 (s, 6H), 2.03 (s, 6H).

C132:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-ethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow oil in 35% yield.¹H-NMR (DMSO-d₆) δ 7.69 (d, 1H), 7.60 (d, 1H), 7.45-7.10 (m, 11H), 4.13(t, 2H), 3.49 (s, 2H), 2.59 (t, 2H), 2.59 (q, 2H), 2.12 (s, 6H), 2.02(s, 6H), 1.98 (t, 3H).

C133:(E)-3-[2′,6′-Dichloro-4-(2-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow oil in 14% yield.¹H-NMR (DMSO-d₆) δ 7.73 (d, 1H), 7.60 (d, 1H), 7.59 (d, 1H), 7.57 (d,1H), 7.46-7.35 (m, 5H), 7.29 (dd, 1H), 7.28 (d, 1H), 7,17 (d, 1H), 4.15(t, 2H), 3.50 (s, 2H), 2.61 (t, 2H), 2.12 (s, 6H), 2.02 (s, 6H).

C134:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′,6′-difluoro-biphenyl3-yl]l-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow crystals in 11%yield. ¹H-NMR (DMSO-d,) δ 7.93 (br s, 1H), 7.65 (d, 1H), 7.52-7.40 (m,6H), 7.35 (d, 1H), 7.25-7.18 (m, 3H), 6.58 (s, 4H), 4.24 (t, 2H), 3.63(s, 2H), 2.83 (t, 2H), 2.27 (s, 6H), 2.13 (s, 6H).

C135:(E)-3-{4-[2-(tert-Butyl-methyl-amino)-ethoxy]-2′-methyl-biphenyl-3-yl}-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 15%yield. ¹H-NMR (CDCl₃) δ 7.48 (d, 1H), 7.33 (d, 1H), 7.22-7.01 (m, 9H),6.90 (d, 1H), 6.76 (d, 1H), 3.92 (bs, 2H), 3.38 (s, 2H), 2.62 (bs, H),2.08 (s, 6H), 1.97 (s, 6H), 0.90 (s, 9H).

C136:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[2′-methyl-4-(2-pyrrolidin-1-yl-ethoxy)-biphenyl-3-yl]-propenone

General procedure H gave the hydrochloride of the title compound asyellow crystals in 55% yield. ¹H-NMR (DMSO-d₆) δ 11.53 (bs, 1H), 9.63(bs, 1H), 8.20 (d, 1H), 8.08 (d, 1H), 8.02 (d, 1H), 7.80-7.65 (m, 4H),7.47 (dd, 1H), 7.34-7.24 (m, 5H), 4.5 (t, 2H), 4.42 (d, 2H), 3.67-3.59(m, 4H), 3.12-3.09 (m, 2H), 2.79 (d, 6H), 2.27 (s, 3H), 2.02-1.89 (m,4H).

C137:(E)-3-[4-(2-Diethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the hydrochloride of the title compound asyellow crystals in 46% yield. ¹H-NMR (DMSO-d₆) δ 11.21 (bs, 1H), 9.71(bs, 1H), 8.20 (d, 1H), 8.07 (d, 1H), 8.02 (d, 1H), 7.82-7.65 (m, 4H),7.47 (dd, 1H), 7.34-7.23 (m, 5H), 4.5 (t, 2H), 4.41 (d, 2H), 3.59-3.57(m, 2H), 3.27-3.19 (m, 4H), 2.79 (d, 6H), 2.27 (s, 3H), 1.30 (t, 6H).

C138:(E)-3-[4-(3-Dimethylamino-propoxy)-2′-methyl-biphenyl-3-yl]-1-(2-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound ascolourless crystals in 7% yield. ¹H-NMR (DMSO-d₆) δ 7.94 (d, 1H), 7.84(t, 1H), 7.74 (d, 1H), 7.64 (dd, 2H),7.39 (dd, 1H), 7.31-7.21 (m, 40),7.18 (d, 1H), 6.98-6.90 (m, 2H), 6.56 s, 2H), 4.19 (t, 2H), 2.71 (t,2H), 2.50 (s, 6H), 2.38 (s, 3H), 2.08-2.03 (m, 2H).

C139:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methoxy-biphenyl-3-yl]-1-(3-fluoro-4-hydroxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 22%yield. ¹H-NMR (DMSO-d₆) δ 8.01-7.86 (m, 5H), 7.53 (dd, 1H), 7.36-7.31(m, 2H), 7.18-7.01 (m,4H), 4.25 (t, 2H), 3.77 (s, 3H), 2.84 (t, 2H),2.34 (s, 6H).

C140:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-fluoro-4-hydroxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 22%yield. ¹H-NMR (CDCl₃) δ 8.26 (d, 1H), 8.12 (d, 1H), 8.03-7.94 (m, 3H),7.72 (dd, 1H), 7.35 (bs, 2H), 7.24 (d, 1H), 7.15 (t, 1H), 7.00 (bs, 1H),4.52 (t, 2H), 3.58 (t, 2H), 2.87 (s, 6H), 2.36 (s, 6H).

C141:(E)-3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(3-fluoro-4-hydroxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 22%yield. ¹H-NMR (CDCl₃) δ 11.00 (s, 1H), 10.69 (bs, 1H), 8.08 (d, 1H),7.99-7.91 (m, 3H), 7.86 (d, 1H), 7.16 (t, 1H), 7.09 (d, 1H), 4.47 (t,2H), 3.59 (t, 2H), 2.88 (s, 6H), 1.34 (s, 9H).

C142:(E)-3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-(3-fluoro-4-hydroxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 46%yield. ¹H-NMR (DMSO-d₆) δ 8.05 (d, 1H), 7.98-7.89 (m, 3H), 7.85 (d, 1H),7.28 (dd, 1H), 7.13 (t, 1H), 7.06 (d, 1H), 4.44 (t, 2H), 3.57 (t, 2H),2.87 (s, 6H), 2.32 (s, 3H).

C143:(E)-3-[2-(2-Dimethylamino-ethoxy)-5-methyl-phenyl]-1-(3-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 12%yield. ¹H-NMR (CDCl₃) δ 8.04 (d, 1H), 7.92-7.84 (m, 3H), 7.77 (d, 1H),7.42 (d, 1H), 7.17 (dd, 1H), 7.05 (t, 1H), 6.87 (d, 1H), 4.17 (t, 2H),3.99 (s, 3H), 2.85 (t, 2H), 2.39 (s, 6H), 2.34 (s, 3H).

C144:(E)-3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(3-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 20%yield. ¹H-NMR (CDCl₃) δ 8.04 (d, 1H), 7.92-7.87 (m, 2H), 7.83 (d, 1H),7.61 (d, 1H), 7.42 (dd, 1H), 7.07 (t, 1H), 6.93 (d, 1H), 4.21 (t, 2H),4.01 (s, 3H), 2.88 (t, 21H), 2.41 (s, 6H), 1.37 (s, 9H).

C145:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(3-fluoro-4-methoxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 20%yield. ¹H-NMR (CDCl₃) δ 7.97 (d, 1H), 7.79-7.66 (m, 4H), 7.44 (dd, 1H),7.06 (bs, 2H), 6.94-6.87 (m, 3H), 4.12 (t, 2H), 3.85 (s, 3H), 2.78 (t,2H), 2.30 (s, 6H), 2.27 (s, 6H).

C146:(E)-3-(2,4-Dichloro-phenyl)-1-[4-(2-dimethylamino-ethoxy)-phenyl]-propenone

General procedure H,gave the title compound as yellow crystals in 36%yield. ¹H-NMR (CDCl₃) δ 7.94 (d, 1H), 7.87 (d, 2H), 7.53 (d, 1H), 7.33(d, 1H), 7.32 (d, 1H), 7.15 (dd, 1H), 6.86 (d, 2H), 4.03 (t, 2H), 2.65(t, 2H), 2.23 (s, 6H).

C147:(E)-3-{4-[5-(tert-Butyl-methyl-amino)-pentyloxy]-2′-methyl-biphenyl-3-yl}-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as yellow/brown oil in 22%yield. ¹H-NMR (CDCl₃) δ 7.43 (d, 1H), 7.31 (d, 1H), 7.19-7.01 (m, 9H),6.90 (d, 1H), 6.72 (d, 1H), 3.82 (t, 2H), 3.34 (s, 2H), 2.14-2.08 (m,5H), 2.00 (s, 3H), 1.93 (s, 6H), 1.61 (m, 2H), 1.28-1.08 (m, 4H), 0.86(s, 9H).

C148:(E)-3-[4-(4-Diethylamino-butoxy)-2′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as yellow/brown oil In 32%yield. ¹H-NMR (CDCl₃) δ 7.52 (d, 1H), 7.37 (d, 1H), 7.28-7.06 (m, 9H),6.99 (d, 1H), 6.80 (d, 1H), 3.92 (t, 2H), 3.42 (s, 2H), 2.43-2.34 (m,6H), 2.14 (s, 3H)) 2.00 (s, 6H), 1.70-1.66 (m, 2H), 1.49 (bs, 2H), 0.92(t, 6H).

C149:(E)-3-{4-[4-(tert-Butyl-methyl-amino)-butoxy]-2′-methyl-biphenyl-3-yl}-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as yellow/brown oil in 65%yield. ¹H-NMR (CDCl₃) δ 7.53 (d, 1H), 7.40 (d, 1H), 7.29-7.10 (m, 9H),7.02 (d, 1H), 6.83 (d, 1H), 3.94 (t, 2H), 3.44 (s, 2H), 2.26 (t, 2H),2.17 (s, 3H), 2.06 (s, 3H), 2.03 (s, 6H), 1.72-1.67 (m, 2H), 1.45-1.40(m, 2H), 0.95 (t, 9H).

C150:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[2′-methyl-4-(4-pyrrolidin-1-yl-butoxy)-biphenyl-3-yl]-propenone

General procedure H gave the title compound as an yellow/brown oil in44% yield. ¹H-NMR (CDCl₃) δ 7.63 (d, 1H), 7.50 (d, 1H), 7.39-7.19 (m,9H), 7.11 (d, 1H), 6.93 (d, 1H), 4.05 (t, 2H), 3.54 (s, 2H), 2.49-2.47(m, 6H), 2.27 (s, 3H), 2.13 (s, 6H), 1.86-1.75 (m, 6H), 1.65-1.60 (m,2H).

C151:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[2′-methyl-4-(4-methylamino-butoxy)-biphenyl-3-yl]-propenone

General procedure H gave the title compound as an yellow oil in 26%yield. ¹H-NMR (DMSO-d₆) δ 7.72 (d, 1H), 7.70 (d, 1H), 7.69-7.21 (m,10H), 7.11 (d, 1H), 6.67 (bs, 1H), 4.07 (m, 2H), 2H), 3.49 (s, 2H), 2.46(t, 2H), 2.26 (s, 3H), 2.02 (s, 6H), 1.75 (s, 3H), 1.72-1.67 (m, 2H),1.51-1.44 (m, 2H).

C152:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(4-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as orange oil in 29% yield.¹H-NMR (CDCl₃) δ 8.25 (d, 1H), 8.14 (d, 2H), 7.85 (d, 1H), 7.72 (d, 1H),7.59 (d, 2H), 7.47-7.37 (m, 5H), 7.13 (d, 1H), 4.42 (t, 2H), 3.69 (s,2H), 3.13 (t, 2H), 2.62 (s, 6H), 2.43 (s, 6H), 2.41 (s, 3H).

C153:(E)-3-[4-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-3-yl]-1-(3-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compound as yellow oil in 64% yield.¹H-NMR (CDCl₃) δ 8.16 (d, 1H), 7.97 (m, 2H), 7.73-7.62 (m, 3H), 7.49,(t, 1H), 7.34 (dd, 1H), 7.30-7.22 (m, 4H), 7.01 (d, H), 4.36 (t, 2H),3.66 (bs, 2H), 3.09 (bs, 2H), 2.57 (bs, 6H), 2.37 (bs, 6H), 2.29 (s,3H).

C154:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[4-hydroxy-2-(4-methyl-piperazin-1-yl)-phenyl]-propenone

General procedure H gave the title compound as yellow oil in 26% yield.¹H-NMR (CDCl₃) δ 8.11 (d, 1H), 7.89 (d, 1H), 7.69 (d, 1H), 7.56 (d, 1H),7.54 (dd, 1H), 7.19 (bs, 2H), 6.99-6.96 (m, 2H), 6.50-6.46 (m, 2H), 4.21(t, 2H), 3.05 (t, 4H), 2.89 (t, 2H), 2.54 (bs, 4H), 2.40 (s, 6H), 2.36(s, 6H), 2.18 (s, 3H).

C155:(E)-3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-[4-(2-dimethylamino-ethoxy)-2-(4-methyl-piperazin-1-yl)-phenyl]-propenone

General procedure H gave the title compound as yellow crystals in 70%yield. ¹H-NMR (CDCl₃) δ 8.01 (d, 1H), 7.62-7.54 (m, 3H), 7.38 (d, 1H),6.62-6.58 (m, 2H), 4.12 (t, 2H), 3.77 (s, 3H), 3.07 (t, 4H), 2.76 (t,2H), 2.50 (bs, 4H), 2.35 (s, 6H), 2.34 (s, 3H), 1.40 (s, 9H), 1.34 (s,9H).

C156:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-(2-fluoro-4-hydroxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 59% yield. ¹H-NMR (DMSO-d₆) δ 7.95 (d, 1H), 7.91 (d, 1H),7.74 (t, 1H), 7.69-7.60 (m, 2H), 7.26 (bs, 2H), 7.18 (d, 1H), 6.96 (bs,1H), 6.75 (dd, 1H), 6.67 (dd, 1H), 6.47 (s,2H), 4.31 (t, 2H), 3.13 (t,2H), 2.53 (s, 6H), 2.30 (s, 6H).

C157:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′,5′-dimethyl-biphenyl-3-yl]-1-[4-(2-dimethylamino-ethoxy)-2-fluoro-phenyl]-propenone

General procedure H gave the title compound as yellow crystals in 36%yield. ¹H-NMR (DMSO-d₆) δ 8.00 (d, 1H), 7.91 (d, 1H), 7.81 (t, 1H), 7.76(d, 1H), 7.71-7.67 (m, 1H), 7.31 (bs, 2h), 7.20 (d, 1H), 7.01-6.91 (m,3H), 4.20 (t, 2H), 4.17 (t, 2H), 2.71 (t, 2H), 2.64 (t, 2H), 2.33 (s,6H), 2.22 (s, 6H), 2.21 (s, 6H).

C158:(E)-3-(2,4-Dichloro-phenyl)-1-[4-(2-dimethylamino-ethoxy)-2-fluoro-phenyl]-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 37% yield. ¹H-NMR (DMSO-d₆) δ 8.05 (d, 1H), 7.91-7.83 (m,2H), 7.75 (d, 1H), 7.60 (dd, 1H), 7.52 (dd, 1H), 7.03-6.93 (m, 2H), 6.58(s, 2H), 4.25 (t, 2H), 2.86 (t, 2H), 2.37 (s, 6H).

C159:(E)-3-(2,4-Dichloro-phenyl)-1-[3-(2-dimethylamino-ethoxy)-phenyl]-propenone,

General procedure H gave the fumarate of the title compound as whitecrystals in 8% yield. ¹H-NMR (DMSO-d₆) δ 8.04 (d, 1H), 7.62 (d, 1H),7.54-7.49 (m, 2H), 7.39 (d, 1H), 7.38 (d, 1H), 7.33 (d, 1H), 7.24 (ddd,1H), 7.19 (s, 2H), 7.10 (ddd, 1H), 4.11 (t, 2H), 2.75 (t, 2H), 2.33 (s,6H).

C160:(E)-3-[5-tert-Butyl-2-(2-dimethylamino-ethoxy)-phenyl]-1-(4-hydroxy-phenyl)-propenone

General procedure H gave the fumarate of the title compound as yellowcrystals in 42% yield. ¹H-NMR (DMSO-d₆) δ 8.05 (d, 2H), 7.95 (, 2H),7.82 (d, 1H), 7.42 (d, 1H), 7.05 (d, 1H), 6.91 (d, 2H), 6.58 (s, 3H),4.24 (t, 2H), 3.00 (t, 2H), 2.46 (s, 6H), 1.32 (s, 9H).

C161:(E)-3-[4-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(4-hydroxy-phenyl)-propenone

General procedure H gave the title compound as yellow crystals in 25%yield. ¹H-NMR (CDCl₃) δ 7.99 (d, 1H), 7.93 (d, 1H), 7.76 (d, 1H), 7.73(s, 1H), 7.52-7.47 (m, 3H), 7.36 (t 2H), 7.28-7.23 (m, 1H), 6.95 (d,1H), 6.84 (dd, 2H), 4.14 (t, 2H), 2.79 (t, 2H), 2.31 (s. 6H).

C162:(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[2′-methyl-4-(5-pyrrolidin-1-yl-pentyloxy)-biphenyl-3-yl]-propenone

General procedure H gave the title product as yellow crystals in 43%yield. ¹H-NMR (CDCl₃) δ 7.57 (d, 1H), 7.43 (d, 1H), 7.36-7,13 (m, 9H),7.05 (d, 1H), 6.86 (d, 1H), 3.97 (t, 2H), 3.48 (s, 2H), 2.72 (bs, 2H),2.57 (bs, 2H), 2.21 (s, 3H), 2.07 (s, 6H), 1.95 (s, 4H), 1.85 (bs, 4H),1.79-1.71 (m, 2H), 1.62 (bs, 2H), 1.43-1.37 (m, 2H),

C163:(E)-3-[2-(2-Dimethylamino-ethoxy)-5-pyridin-3-yl-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow oil in 25% yield.¹H-NMR (DMSO-d₆) δ 8.74 (d, 1H), 8.51 (dd, 1H), 7.77 (dt, 1H), 7.69 (d,1H), 7.56 (d, 1H), 7.48 (dd, 1H), 7.36-7.26 (m, 5H), 7.13 (d, 1H), 6.94(d, 1H), 4.09 (t, 2H), 3.53 (s, 2H), 2.67 (t, 2H), 2.20 (s, 6H), 2.10(s, 6H).

C164:(E)-3-[2-(2-Dimethylamino-ethoxy)-5-pyridin-2-yl-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow oil in 48% yield.¹H-NMR (CDCl₃) δ 8.61-8.58 (m, 1H), 8.16 (d, 1H), 7.92 (dd, 1H),7.68-7.56 (m, 3H), 7.43-7.12 (m, 6.93 (d, 1H), 4.11 (t, 2H), 3.57 (s,2H), 2.69 (t, 2H), 2.22 (s, 6H), 2.14 (s, 6H).

C165:(E)-3-[4-(2-Dimethylamino-ethoxy)-3′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as yellow crystals in 12%yield. ¹H-NMR (DMSO-d₆) δ 11.40 (bs, 1H), 9.93 (bs, 1H), 8.24 (d, 1H),8.15 (dd, 1H), 8.03 (d, 1H), 7.99-7.67 (m, 5H), 7.54 (d, 2H), 7.34 (d,1H), 7.28 (d, 1H), 4.58 (t, 2H), 4.43 (d, 2H), 3.59-3.55 (m, 2H), 2.82(d, 6H), 2.78 (d, 6H), 2.39 (s, 3H).

C166:(E)-3-[3-(2-Dimethylamino-ethoxy)-2′-methyl-biphenyl-4-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General Procedure H gave the title product at yellow oil in 32% yield.¹H-NMR (DMSO-d₆) δ 7.81 (d, 1H), 7.57 (d, 1H), 7.47-7.40 (m, 2H),7.40-7.34 (m, 2H), 7.33-7.20 (m, 5H), 7.01 (d, 1H), 6.96 (dd, 1H), 4.12(t, 2H), 3.50 (s, 2H), 2.55 (t, 2H), 2.27 (s, 3H), 2.09 (s, 6H), 2.04(s, 6H).

C167:(E)-3-[2′-Bromo-4-(2,-dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title product as brown oil in 8% yield. ¹HNMR (300 MHz, CDCl₃): δ 7.62-7.57 (m, 4H), 7.44-7.06 (m, 8H), 6.89 (d,1H), 4.12 (bs, 2H),3.60 (s, 2H), 2.72 (bs, 2H), 2.36 (s, 6H), 2.17 (s,6H).

C168:(E)-3-[4-(2-Dimethylamino-ethoxy)-4′-methyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the hydrochloride of the title product asyellow crystals in 57% yield. ¹H-NMR (300 MHz, DMSO-d₆) δ 11.93 (br,1H), 10.31 (br, 1H), 8.00 (d, 1H), 8.00-7.95 (m, 1H), 7.89 (d, 1H),7.87-7.83 (m, 1H), 7.63-7.56 (m, 3H); 7.50 (d, 1H), 7.42 (d, 2H), 7.18(s, 2H), 7.08 (d, 1H), 4.57 (t, 2H), 4.44 (d, 2H), 3.59 (dt, 2H1), 2.88(d, 6H), 2.83 (d, 6H), 2.31 (s, 3H).

C169:(E)-3-[5-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone

General procedure H gave the title compounds as a yellow oil in 60%yield. ¹H-NMR (DMSO-d₆): δ 7.74 (bd, 2H), 7.60 (bs, 1H), 7.48-7.30 (m,10H), 7.24 (t, 1H), 4.17 (t, 2H), 3.53 (s, 2H), 2.64 (t, 2H), 2.23 (s,6H), 2.03 (s, 6H).

Determination of Metabolic Stability

Incubations were performed with Wistar rat liver microsomes (0.25 mg/ml)in 2% sodium bicarbonate solution. NADP (0.13 mg/ml),glucose-6-phosphate (0.63 mg/ml) and glucose-6-phosphate dehydrogenase(0.38 units/ml) were used as NADPH generation system and UDPGA (0.48mg/ml) was added to include the phase II reaction, glucuronic acidconjugation, in the assay. After 5 minutes of pre-incubation thereaction was started by addition of the test article to give a finalconcentration of 20 μM. Samples were incubated for 15 min at 37° C. andthe reactions were terminated by addition of equal volumes ofacetonitrile. Blank incubations were performed at the same concentrationbut without addition of microsomes. Both blank and microsome-containingsamples were made in replicats of three. Prior to analysis samples werecentrifuged for 10 min. at 3500 rpm,HPLC system:

The fraction of compound metabolised during the 15 min of incubation wasdetermined by comparison of blank and microsome-containing samples usinga Waters Alliance 2690 separation module and Waters 996PDA-detector(Waters. Milford, Mass., USA.) Separation was performed on aXTerra MS C₁₈ column (150*2.1 mm I.D., 3,5 μm particle size) (WatersMilford, Mass., USA) by. Initial conditions were 40% mobile phase A(acetonitrile) and 60% mobile phase B (10 mM ammonium acetate pH 9.5).During the first 20 minutes, the mobile phase was changed via a lineargradient to 90% A and 10% B. This was followed by a 5 minutes lineargradient to initial conditions, which were maintained for 5 min. Theflow rate was 0.20 m)/min and injection volume 10 μl.

Determination of Solubility

Solubility of the compounds was determined by preparing a saturatedsolution of compound in 0.3 M phosphate buffer (pH 7.4±0.3) in a brownglass tube. The suspensions were rotated slowly for 24 hours. Aliquotswere centrifuged for 10 minutes at 14.000 rpm and supernatants werediluted in 40% (v/v) acetonitrile in water prior to HPLC analysis.Concentrations of analytes were quantified against a standard curve andused as term of solubility. The HPLC-UV method used for the assessmentof solubility is the same as used in the in vitro metabolism assay.

Pharmacokinetic Studies

Evaluation of the pharmacokinetic properties of the compounds was doneusing female NMRI mice (weighing app. 30 g). Test articles wereadministrated intravenously and orally as a cassette dose formulationscontaining three compounds or as individual compounds. Samples of serumwere taken at defined timepoints.

Standards and QC-samples in plasma were prepared and the serumconcentrations of the test compounds quantified by HPLC-MS.

Prior to analysis, proteins were precipitated by deluding the samples(1:1) (v/v) with 100% acetonitrile followed by centrifugation at 14.000rpm in 10 min. The supernatant was used for the analysis.

HPLC-MS System:

A Waters Alliance HPLC-system (Milford, Mass., USA) was coupled to aQuatro Micro triple quadropl mass spectrometer (Micromass, Manchester,UK) operating in positive (ESI) mode. Separation was performed on aXTerra MS C₁₈ column (150*2.1 mm I.D., 3,5 μm particle size) (WatersMilford, Mass., USA).

Mobile phase A: 0.1% (v/v) formic acid or 10 mM ammonium acetatepH-adjusted to 9.5 in MilliQ-water, mobile phase B: 100% methanol. Thegradient was as follows: 0-min=70% A−30% B, 0-10 min. a linear gradientto 10% A and 90% B this was maintained till 11 min, 11-13 lineargradient to 70% A and 30% B this was maintained till 18 min. The flowrate was 0.20 m/min, injection volume 10 μl.

Biological Testing

General Methods

In vitro Microbiological Testing

MIC Determination in Broth Microdilution Assay

Compounds were screened for activity against a panel of 10 differentnon-fastidious bacteria growing aerobically (Staphylococcus aureusATCC29213; Staphylococcus aureus ATCC33591;Staphylococcus intermedius#2357(clinical isolate from the Copenhagen area); Enterococcus faecalisATCC29212;Enterococcus faecium #17501 (vancomycin-resistant clinicalisolate); Streptococcus pneumoniae #998 (clinical isolate);Streptococcus pyogenes #14813 (clinical isolate); Streptococcusagalactiae #19855 (clinical isolate); Eschericia coli ATCC25922 andEschericia coli ESS). The screening assay was done in 200 μl MH-brothcultures in microtitre plates. For compounds exhibiting activity in theinitial screen MIC was determined in a microdilution assay usingMH-broth as described by NCLLS (National Committee for ClinicalLaboratory Standards. Methods for Dilution Antimicrobial SusceptibilityTests for Bacteria That Grow Aerobically; Approved Standard—FifthEdition. M7-A5 NCCLS 2000) modified to include uninoculated dilutionseries of test compounds to facilitate MIC determination if the testcompound should precipitate. MIC was determined as the lowestconcentration of test compound able to inhibit visible growths ofbacteria. MICs for ATCC type strains fell within the limits posted bythe NCCLS (National Committee for Clinical Laboratory Standards.Performance Standards for Antimicrobial Susceptibility Testing; EleventhInformational Supplement. M100-S11 NCCLS 2001) when tested againstvancomycin, tetracycline, gentamycin.

MIC and MBC Determination in Broth Macrodilution Assay

MIC and MBC of test compounds were determined in a broth macrodilutionassay using 2 ml MH-broth cultures and an inoculum of approximately5×10E5 CFU/ml as described by Amsterdam (Amsterdam, D. Susceptibilitytesting of antimicrobials in liquid media. In V. Lorian (ed.):Antibiotics in Laboratory Medicin 4. edition. Williams & Wilkins 1996).MIC was determined as the minimal concentration of test compound able toinhibit visible growth of bacteria. Samples from cultures inhibited bytest compound were plated onto unselective blood agar plates. MBC wasdetermined as the minimal concentration of test compound able todecrease colony count on these plates below 0.1% compared to theoriginal inoculum.

Killing Curve Determination

For the determination of the killing curve of a test compound a dilutionseries of test compound was made and inoculated with approximately5×10E5 CFU/ml as described for the MIC macrodilution assay above. At thetimepoints indicated 100 μl samples was withdrawn from the test tubes,serially diluted and spotted in duplicate on unselective agar plates todetermine CFU. Test compounds with bactericidal activity is capable ofdecreasing surviving colony counts (CFU/ml) when incubated withbacteria. Bactericidal activity may be either primarily dependent onconcentration of test compound or on incubation time with test compound.An example of a bactericidal compound (C023), which is primarilydependent on the concentration of the test compound is shown in FIG. 2.An example of a bactericidal compound (C030) which is primarilydependent on the incubation time with the compound is shown in FIG. 3.

MIC Determination Against Helicobacter pylori

Six strains of Helicobacter pylori were used in an agar dilution assayaccording to the standards of NCCLS (National Committee for ClinicalLaboratory Standards. Methods for Dilution Antimicrobial SusceptibilityTests for Bacteria That Grow Aerobically; Approved Standard—FifthEdition. M7-A5 NCCLS 2000). MH-agar plates supplemented with 5% horseblood and containing a dilution series of the test compound wereinoculated in duplicate with 10 μl spots of a 2 McF suspension of thedifferent strains of H.pylori. This inoculum corresponds toapproximately 10E6 CFU/spot. Plates were then incubated in amicroaerophilic atmosphere at 35° C. for 72 hours. The MIC endpoint wasdetermined as the lowest concentration of test compound able tocompletely inhibit or most significantly reduce growth compared togrowth control plates not containing test compounds.

Activity Determination Against Anaerobic Bacteria

Screening for activity against anaerobic bacteria was done against twoisolates of Bacteroides fragilis, an isolate of Clostridium difficileand an isolate of Clostridium perfringens in an agar dilution assay asdescribed by NCCLS (National Committee for Clinical LaboratoryStandards. Methods for Antimicrobial Susceptibility Testing of AnaerobicBacteria; Approved Standard—Fifth Edition. M11-A5 NCCLS 2000) with theexception that Mueller-Hinton agar was used in place of supplementedBrucella broth. Plates containing test compound at a singleconcentration (either 100 or 150 μM) were prepared in duplicate alongwith appropriate control plates. Activity was present if growth in thepresence of test substance was absent or most significantly reducedcompared to growth control plates not containg test compound.

Leishmania Promastigote Assay

A WHO reference vaccine strain of L.major originally isolated from apatient in Iran were cultured in Medium 199 with Hanks' Salts containing0.02 mg/ml gentamycin, 25 mM HEPES, 4 mM L-glutamine, and 10% heatinactivated fetal calf serum (FCS). Incubation was carried out at 27° C.Promastigotes were harvested at day 3 of culture and used for the assayof inhibition of parasite growth.

The effect of test compounds on promastigotes was assessed by a methodmodified from Pearson et al. Briefly, promastigotes (0.8×10⁶/well) wereincubated in 200 μl duplicate cultures either with a dilution series oftest compound or medium alone In 96 wells flat buttom microtiter plates.After 2 h of incubation, 1.5 μCi of 3H-thymidine was added to each welland further incubated for 18 hours. The cultures were then harvested onUnifilter-GF/C microtiter filter plates (Packard Instruments), washedextensively and counted in a TopCount-NXT microplate scintillationcounter (Packard Instruments).

Plasmodium falciparum Assay

Plasmodium falciparum 3D7 was maintained in culture by a modification ofthe method originally described by Trager and Jensen. In brief, theparasites were grown in suspensions of human blood group 0 erythrocytes(RBC) maintained in RPM11640 medium supplemented with 4.5 g/l Albumax II(Invitrogen), 10 mM hypoxantine, 1.4 mM L-glutamine and 0.05 mg/mlgentamicin. Cultures were incubated at 37° C. in atmosphere of 92.5%nitrogen, 5.5% carbon dioxide, and 2% oxygen. To obtain synchronizedcultures og parasites erythrocytes infected with late trophozoite andschizont stages were separated from ring stages and uninfected RBC bymagnet-activated cell sorting (MACS; Miltenyi BioTec) (Staalsoe, T., H.A. Giha, D. Dodoo, T. G. Theander, and L. Hviid. 1999. Detection ofantibodies to variant antigens on Plasmodium falciparum-infectederythrocytes by flow cytometry. Cytometry 35:329-336). Because of theirhigh content of paramagnetic haemozoin, erythrocytes infected with latedevelopmental stages of malaria parasites are specifically retainedwithin the column. The column was washed with PBS supplemented with 2%foetal calf serum and then the column was removed from the magnet andthe retained late developmental stages of parasites were eluted andcultured for an additional 18 hours. At this time the culture is highlysynchronous containing more than 90% ring stages.

These synchronized cultures of ring stage parasites were used to assayfor antimalarial parasites. Briefly, cultures of ring stage parasiteswere adjusted to 1% parasitemia by addition of uninfected RBC. Then,these were incubated in 12 μl duplicate cultures containing 2.5×10⁷RBC/well with either a dilution series of test compound or with mediumalone. Plates were then incubated at 37° C. for 24 hours when cultureswere labelled by the addition 1.1 μCi 3H-phenyalanine and incubatedovernight. Then, the cultures were harvested on Unifilter-GF/Cmicrofilter plates (Packard Instruments) and washed extensively withwater followed by a wash with 10% H₂O ₂ to bleach hemoglobin. Filterplates were counted in a TopCount-NXT microplate scintillation counter(Packard Instruments).

DHODH Assay

100 μl chalcone or 0.1 M Tris-HCl pH 8.0 is added to a well in a96-wells microtiter plate. Then 50 μl enzyme dilution is added. Themicrotiter plate is placed in the Powerwave_(x)340 and the enzymaticreactions starts when adding 100 μl assay mixture. The reaction aremeasured every 20 sec. for 10 min. The samples with chalcones arecompared with the samples with 0.1 M Tris-HCl pH 8.0 and the percentinhibition is calculated.

Enzyme dilution: The solution of recombinant purified enzyme isdissolved in 0.1 M Tris-HCl pH 8 to give an initial velocity of0.04-0.05 ΔA/min.

2,6-dichlorophenolindophenol (DCIP)-stock solution: 40 mg DCIP and 10 ml99% Ethanol are mixed for 10 min at RT. Then 100 μl 1.0 M Tris-HCl pH 8and miliQ H2O are added to a final volume of 100 ml. The A₆₀₀ of theDCIP-stock solution are measured in a microtiter plate on thePowerwave_(x)340 (Bio-Tek instruments,Inc.)

Dihydroorotate dehydrogenase (DHODH)-stock solution: 25 mMdihydroorotate stock-solution is prepared by first dissolving in thesame amount of mol NaOH and then miliQ H₂O is added to the final volume.

Assay mix (10 ml solution): 600 μl of DHODH-stock solution and X ml(depending on the A₆₀₀ value of stock-solution) DCIP to a final A₆₀₀=2.5are mixed. Then 0.1 M Tris-HCl pH 8.0 are added to a final volume of 10ml.

Preparation of compound soluton: A 10 mM stock-solution of compound(e.g. a chalcone derivative) is made in dimethylsulfoxid (DMSO). Thecompound is then diluted in 0.1 M Tris-HCl pH 8 to the testconcentrations. The final DMSO concentration in the sample is 10%

Biological Results

Licochalcone A (LicA) and 4′-methoxy chalcone (4′MC) described in WO93/17671 are used as reference compounds in the following discussion.

Activity Against Non-fastidious Bacteria

Licochalcone A exhibits moderate bactericidal activity against commonpathogenic Gram-positive non-fastidious bacteria includingStaphylococcus aureus, Enterococcus faecalis, Enterococcus faecium,Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcusagalactiae. Licochalcone A maintains its activity also againstantibiotic resistant bacteria, e.g. Staphylococcus aureus ATCC33591(resistant to methicillin) and Enterococcus faecium #17051 (resistant tovancomycin). In contrast, Licochalcone A has only modest or no activityagainst the prototype,pathogenic Gram-negative bacterium, Eschericiacoli. 4′MC as a representative of non-hydroxyl chalcones exhibits noantibacterial effect at all.

In comparison with Licochalcone A, aminoalkoxy-functional chalconesretain the activity of Licochalcone A against pathogenic Gram-positivebacteria including antibiotic-resistant strains (cf. Table 1). Theaminoalkoxy-functional chalcones exhibit increased potency againstGram-positive pathogens (e.g. C004, C015, C023, C030, C037, C042). Incontrast to Licochalcone A, aminoalkoxy-functional chalcones exhibitactivity against Eschericia coli. Thus, several aminoalkoxy-functionalchalcones (e.g. C074, C075, C103) exhibit high activity against E coliATCC25922 and against the generally more susceptible ESS strain ofE.coli (cf. Table 1). This indicates the potential use ofaminoalkoxy-functional chalcones in the treatment of infectionsassociated with Gram-negative bacteria.

In the treatment of severe infections in immunocompromised patientsbacteriocidal action of an antibiotic is a necessity. As exemplified inFIGS. 2 and 3, aminoalkoxy chalcones retain the bactericidal action ofLicochalcone A. For aminoalkoxy chalcones the bactericidal action ispredominantly dependent on the concentration of the compound (e.g. C023and C030; cf. FIGS. 2 and 3). This knowledge is helpful when designingdosing regimens for in vivo efficacy trials.

TABEL 1 Comparison of the effect of aminoalkoxy-chalcones andLicochalcone/4′MC on bacteria; MIC values in μM. A B C D E F G H LICA37.5 37.5 37.5 37.5 37.5 75.0 300.0 4′-MC NA NA NA NA NA NA NA NA C0049.4 9.4 18.8 18.8 18.8 18.8 75.0 9.4 C023 4.7 4.7 4.7 4.7 4.7 18.8 9.4C039 9.4 18.8 18.8 18.8 18.8 18.8 75.0 9.4 C074 9.4 9.4 9.4 9.4 9.4 9.44.7 C075 4.7 4.7 9.4 9.4 9.4 9.4 4.7 C085 4.7 4.7 4.7 4.7 4.7 75 4.7C157 4.7 9.4 9.4 9.4 9.4 9.4 18.8 4.7 C089 9.4 9.4 18.8 9.4 9.4 9.7 37.54.7 C092 4.7 9.4 18.8 4.7 4.7 4.7 75 4.7 C093 4.7 4.7 4.7 9.4 4.7 18.84.7 C072 9.4 18.8 9.4 18.8 18.8 37.5 9.4 C103 4.7 4.7 9.4 9.4 9.4 18.84.7 C104 9.4 18.8 18.8 9.4 9.4 9.4 18.8 9.4 C067 4.7 4.7 4.7 4.7 4.718.8 18.8 A: Staphylococcus aureus ATCC29213; B: Staphylococcus aureusATCC33591(resistant to methicillin); C: Staphylococcus intermedius#2357(clinical isolate from the Copenhagen area); D: Enterococcusfaecalis ATCC29212; E: Enterococcus faecium #17501 (vancomycin-resistantclinical isolate); F: Streptococcus pneumoniae #998 (clinical isolate);G: Eschericia coli ATCC25922 and H: Eschericia coli ESS. NA: noactivity.Activity Against Helicobacter pylori

Colonisation of the gastric mucosa with Helicobacter pylori is animportant pathogenic determinant for the development of gastritis andpeptic ulcer. Aminoalkoxychalcones exhibit activity against Helicobacterpylori. Several aminoalkoxychalcones (e.g.C004, C010, C014, C022, C030,C088, C094) exhibit MICs in the range between 12 μM and 25 μM whentested against a panel of six strains Helicobacter pylori, that includesstrains resistant to metronidazole. Metronidazol is an antibioticcommonly included in treatment regimens designed to eradicateHelicobacter colonization for the treatment of peptic ulcer. Theactivity of aminoalkoxychalcones against both metronidazole-resistantand sensitive Helicobacter pylori clearly indicates the potential use ofthese compounds in the treatment of Helicobacter infections.

Activity Against Anaerobic Bacteria

Aminoalkoxychalcones have been assayed in a single concentration ofcompound (100 μM) for activity against a panel of anaerobic bacteriacontaining common human pathogenic bacteria (Bacteroides fragilis,Clostridium perfringens, Clostridium difficele). Severalaminoalkoxychalcones (e.g. C015, C025, C026, C028 and C042, C074, C079)exhibit activity against all microorganisms within the test panel. Thisclearly indicates the potential use of aminoalkoxychalcones in treatmentof infection caused by anaerobic bacteria.

Activity Against Protozoa

Activity Against Plasmodium falciparum

Plasmodium falciparum is a protozoan parasite transmitted by themosquito Anopheles, and causing malignant or severe malaria in humans.Licochalcone A exhibits activity against Plasmodium falciparum in vitroand protects mice from infection with P.yoelii and P.berghei (Chen etal., 1994). Aminoalkoxychalcones exhibit activity in vitro againstPlasmodium falciparum and several aminochalcones exhibit improvedpotency compared to Licochalcone A (cf. Table 2 and FIG. 4).Furthermore, the compounds are potent against chloroquine resistantparasites as shown in Table 3. The results clearly indicate thepotential use of aminoalkoxychalcones in the treatment of malaria.

TABLE 2 Activity against Plasmodium falciparum 3D7. Comp. LicA 4′MC C032C035 C036 C038 C160 C075 C156 C090 C130 C131 IC₅₀ (μM) 6.4 40.0 0.5 0.10.2 0.2 0.3 0.5 0.1 0.5 0.03 0.3

TABLE 3 Activity against resistant strains of Plasmodium falciparum.Plasmodium falciparum IC₅₀ (μM) 3D7(Cq-sen) DD2(Cq-res) 7G8(Cq-res)K1(Cq-res) C130 0.03 0.06 0.05 0.04 Chloroquine 0.13 1.0 1.09 >1.56Activity Against Leishmania major

Leishmania major is a protozoan parasite transmitted by the sandflyPhlebotomus, and causing cutaneous leishmaniasis or kala-azar in humans.Licochalcone A exhibits activity against Leishmania parasites and hasshown efficacy in experimental animal models of cutaneous and visceralLeishmania infection (Chen et al., 1994). Aminoalkoxychalcones exhibitactivity in vitro against Leishmania major with significantly improvedpotency compared to Licochalcone A and 4′MC (cf. Table 4). The resultsclearly indicate the potential use of aminoalkoxychalcones in thetreatment of Leishmania infection.

TABLE 4 Effect of aminoalkoxy-chalcones on L. major. Comp. LicA 4′MCC004 C011 C015 C020 C024 C032 C037 C042 C140 IC₅₀ (μM) 4.6 5.6 0.2 0.10.1 0.03 0.04 0.7 0.5 0.2 0.2Inhibition of DHODH

Several of the aminoalkoxy-chalcones prepared are potent inhibitors ofDHODH. The compounds are as potent as LicA and by far more potent thanordinary chalcones exemplified by 4′MC.

TABLE 5 Inhibition of DHODH at 10 μM. Comp. LicA 4′MC C019 C020 C022C026 C027 C028 Inhibition 25% 7% 18% 18% 21% 19% 22% 23%Metabolism

The usefulness of chalcones as drug candidates have been limited by themetabolism of the compounds resulting in short half-lives in vivo (Lica:100% turn-over in vitro and t_(1/2)=10 min in vivo).

The introduction of a aminoalkoxy group in the chalcone changes themetabolic properties; this is clear from Table 6 where the metabolicturn-over of a number of aminoalkoxy-chalcones are compared to LicA. Theaminoalkoxy-chalcones prepared are expected to show low or no metabolismin vivo as the metabolic turn-over are between 0-10% (compared to 100%turn-over for Lica). Consequently the half-life of aaminoalkoxy-chalcone will be longer, reducing the dose needed fortreatment.

TABLE 6 Metabolic turn-over (rat) in vitro (%). Comp. LicA C130 C024C074 C075 C089 C092 C071 Turn-over 100% 6% 3% 7% 8% 9% 4% 3%Solubility

The aqueous solubility of the neutral chalcones described in WO 93/17671is very low. A representative chalcone 4′-methoxy-chalcone has asolubility of <<0.05 mg/ml. A few chalcones have a higher solubility dueto (metabolically unstable) hydroxyl groups in the molecule. LicA has asolubility of approximately 0.01 mg/ml.

The aminoalkoxy-chalcones described in this application are superiorhaving solubility numbers in sub-mg/ml. Representative examples areshown in table 7.

TABLE 7 Solubility in aqueous buffer at pH 7.4. Comp. C018 C036 C037C075 C108 C136 C073 Solubility (mg/ml) 1.5 1.8 1.5 4.1 18.1 5.5 >10

The high aqueous solubility means that dissolution and hence absorptionwill be no problem. This will inevitably cause a dramatic reduction ofthe dose needed making the aminoalkoxy-chalcones very usefull as drugcandidates.

Bioavailability

The bioavailability of the aminoalkoxy chalcones are markedly higherthan seen for LicA. The compound C043 has a bioavailability of 42% inmice compared with <6% for LicA.

Bioavailabiblity

The bioavailability of the aminoalkoxy chalcones in mice is in generallyvery high (e.g. ⁴²% for C043). As the mouse is a very fast metabolizerof the amino chalcones, compared to rat and human (e.g. C130 mice: 77%;rat:. 6%; human: in general lower than rat), the bioavailability in ratand man is expected to be even higher due to limited first passmetabolism.

In vivo Results

A number of amino-chalcones have significant effect in the in vivomodels. As illustrated in FIGS. 6 and 7, the compounds cause asignificant reduction of parasitaemia in plasmodium infected mice,showing the potential of the compounds as drug candidates.

CONCLUSION

The use of chalcones as drug candidates for the treatment of parasiticor bacterial infections has been limited by the low in vivo potency(50mg/kg for LicA) of the compounds and a narrow spectrum of activity.

Several factors contribute to the low in vivo potency: Fast metabolismresulting in short half-lives in vivo; low/no solubility in theintestine and consequently low/no absorption; and medium potency of thecompounds against parasites and no activity against bacteria (except forLicA).

The aminoalkoxy-chalcones in this application are expected to fulfillthe criteria for a drug candidate. The metabolism is slow, thesolubility is High and the compounds are potent against parasites aswell as (resistant) Gram positive and Gram negative bacteria.

1. A compound of the formula(Y¹)_(m)—Ar¹(X¹)—C(═O)VAr²(X²)—(Y²)_(p) and salts thereof, wherein Ar¹and Ar² are aryl; V designates —CH═CH—, m is 0, p is 1, Y¹ is notpresent, Y² represents an aminoalkoxy-functional substituent of theformula—O-Z-N(R¹)R², wherein Z is a biradical —(C(R^(H))₂)_(n)—, wherein n is 2and R^(H) is hydrogen; R¹ and R² are independently selected fromoptionally substituted C₁₋₁₂-alkyl; X¹ designates a substituent present1 time and X² designates a substituent present 1 time, wherein X¹ and X²are independently selected from the group consisting of optionallysubstituted C₁₋₁₂-alkyl and optionally substituted aryl.
 2. The compoundof claim 1, wherein R¹ and R² are independently selected from optionallysubstituted C₁₋₆-alkyl.
 3. The compound of claim 1, wherein X¹ and X²are independently selected from the group consisting of optionallysubstituted C₁₋₆-alkyl and optionally substituted aryl.
 4. The compoundof claim 1, wherein at least one of Ar¹ and Ar² is phenyl.
 5. Thecompound of claim 1, wherein Ar¹ and Ar² are phenyl, Y² is located inthe 2-position of Ar², and X² is located in the 4- or 5-position of Ar².6. The compound of claim 1, wherein R¹ and R² are independently selectedfrom C₁₋₆-alkyl.
 7. The compound of claim 6, wherein Ar¹ and A² arephenyl.
 8. The compound of claim 1 selected from3-[4-(2-Dimethylamino-ethoxy)-2′-trifluoromethyl-biphenyl-3-yl]-1-(2-dimethylaminomethyl-phenyl)-propenone,and salts thereof.
 9. A composition comprising a compound of claim 1 anda pharmaceutically acceptable carrier.
 10. A method for treatingbacterial infections in a mammal comprising administering to the mammala compound of claim
 1. 11. A method for treatment of infectionsassociated with protozoa in a mammal comprising administering to themammal a compound of claim 1.